GPBP inhibition using Q2 peptidomimetics

ABSTRACT

Disclosed are compounds of formula: 
                         
that inhibiting GPBP activity, making them useful as therapeutics in antibody-mediated disorders, drug-resistant cancer, inflammation, protein misfolding and ER stress-mediated disorders, and aberrant apoptosis.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.12/940,598, filed Nov. 5, 2010, which claims the benefit of priority ofU.S. Provisional Application No. 61/258,432, filed Nov. 5, 2009, bothincorporated by reference herein in their entirety.

BACKGROUND OF THE INVENTION

The conformation of the non-collagenous (NC1) domain of the α3 chain ofthe basement membrane collagen IV [α3(IV)NC1] depends in part onphosphorylation. Goodpasture Antigen Binding Protein (GPBP) (WO00/50607; WO 02/061430) is a non-conventional protein kinase thatcatalyzes the conformational isomerization of the α3(IV)NC1 domainduring its supramolecular assembly, resulting in the production andstabilization of multiple α3(IV)NC1 conformers in basement membranes.Increased expression levels of GPBP have been associated with theproduction of aberrant non-tolerized α3(IV)NC1 conformers, which conductthe autoimmune response mediating Goodpasture (“GP”) syndrome. In GPpatients, autoantibodies against the α3(IV)NC1 domain (“Goodpastureantigen” or “GP antigen”) cause a rapidly progressive glomerulonephritisand often lung hemorrhage, the two cardinal clinical manifestations ofthe GP syndrome. Furthermore, it has been proposed that GPBP regulatesinflammation, apoptosis and protein folding, and that increased GPBPexpression induces antibody-mediated glomerulonephritis (IgAnephropathy, systemic lupus erythematosus and Goodpastute autoimmunesyndrome) and resistance of cancer cells to a number of chemotherapeuticagents including those (i.e. paclitaxel) inducing proteinmisfolding-mediated endoplasmic reticulum (ER) stress Thus, inhibitorsof GPBP are useful for the treatment of antibody-mediated disorders,drug-resistant cancer, inflammation, protein misfolding and ERstress-mediated disorders, and aberrant apoptosis.

SUMMARY OF THE INVENTION

A first aspect of the invention provides compounds of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

-   R is selected from N and CR₅;    -   R₅ is selected from the group consisting of hydrogen, halogen,        cyano, nitro, hydroxy, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, halo(C₁-C₆ alkyl), C₁-C₆ alkoxy, halo(C₁-C₆ alkoxy),        amino, (C₁-C₆ alkyl)amino, di(C₁-C₆ alkyl)amino, hydroxy(C₁-C₆        alkyl), (C₁-C₆ alkoxy)C₁-C₆ alkyl, amino(C₁-C₆ alkyl),        sulfanyl(C₁-C₆ alkyl), (C₁-C₆ alkyl)sulfanyl(C₁-C₆ alkyl),        —(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy), —(CH₂)₁₋₅—C(O)NH₂, (aryl)C₂-C₆        alkyl, and (heteroaryl)C₁-C₆ alkyl;-   R₁ is hydrogen, halogen, hydroxy, C₁-C₆ alkyl, halo(C₁-C₆ alkyl),    C₁-C₆ alkoxy, halo(C₁-C₆ alkoxy), hydroxy(C₁-C₆ alkyl), (C₁-C₆    alkoxy)C₁-C₆ alkyl, amino(C₁-C₆ alkyl), sulfanyl(C₁-C₆ alkyl), or    (C₁-C₆ alkyl)sulfanyl(C₁-C₆ alkyl);-   R₂ is C₁-C₆ alkyl, halo(C₁-C₆ alkyl), C₁-C₆ alkoxy, halo(C₁-C₆    alkoxy), hydroxy(C₁-C₆ alkyl), (C₁-C₆ alkoxy)C₁-C₆ alkyl,    formyl(C₀-C₆ alkyl), amino(C₁-C₆ alkyl), sulfanyl(C₁-C₆ alkyl),    (C₁-C₆ alkyl)sulfanyl(C₁-C₆ alkyl), —(CH₂)₁₋₅—C(O)OH,    —(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy), —(CH₂)₁₋₅—C(O)NH₂, (aryl)C₁-C₆ alkyl,    or (heteroaryl)C₁-C₆ alkyl;-   R₃ is C₁-C₆ alkyl, halo(C₁-C₆ alkyl), C₁-C₆ alkoxy, halo(C₁-C₆    alkoxy), hydroxy(C₁-C₆ alkyl), (C₁-C₆ alkoxy)C₁-C₆ alkyl,    formyl(C₁-C₆ alkyl), amino(C₁-C₆ alkyl), sulfanyl(C₁-C₆ alkyl),    (C₁-C₆ alkyl)sulfanyl(C₁-C₆ alkyl), —(CH₂)₁₋₅—C(O)OH,    —(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy), —(CH₂)₁₋₅—C(O)NH₂,    —(CH₂)₁₋₅—C(O)NH(C₁-C₆ alkyl), —(CH₂)₁₋₅—C(O)N(C₁-C₆ alkyl)₂,    —CH═CH—C(O)OH, —CH═CH—C(O)(C₁-C₆ alkoxy), (aryl)C₁-C₆ alkyl, or    (heteroaryl)C₁-C₆ alkyl; and-   R₄ is hydroxy, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆    alkoxy), benzyloxy, —(CH₂)₁₋₅—C(O)OH, —(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy),    —(CH₂)₁₋₅—C(O)NH₂, —(CH₂)₁₋₅—C(O)NH(C₁-C₆ alkyl),    —(CH₂)₁₋₅—C(O)N(C₁-C₆ alkyl)₂, —CH═CH—C(O)OH, —CH═CH—C(O)(C₁-C₆    alkoxy), —O(CH₂)₁₋₅—C(O)OH, —O(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy),    (aryl)C₁-C₆ alkyl, or (heteroaryl)C₁-C₆ alkyl.

A second aspect of the invention provides compounds of formula (V):

or a pharmaceutically acceptable salt thereof, wherein:

-   R is selected from N and CR₅;    -   R₅ is selected from the group consisting of hydrogen, halogen,        cyano, nitro, hydroxy, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, halo(C₁-C₆ alkyl), C₁-C₆ alkoxy, halo(C₁-C₆ alkoxy),        amino, (C₁-C₆ alkyl)amino, di(C₁-C₆ alkyl)amino, hydroxy(C₁-C₆        alkyl), (C₁-C₆ alkoxy)C₁-C₆ alkyl, amino(C₁-C₆ alkyl),        sulfanyl(C₁-C₆ alkyl), (C₁-C₆ alkyl)sulfanyl(C₁-C₆ alkyl),        —(CH₂)₁₋₅—C(O)OH, —(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy),        —(CH₂)₁₋₅—C(O)NH₂, (aryl)C₁-C₆ alkyl, and (heteroaryl)C₁-C₆        alkyl;-   R₁ is hydrogen, halogen, hydroxy, C₁-C₆ alkyl, halo(C₁-C₆ alkyl),    C₁-C₆ alkoxy, halo(C₁-C₆ alkoxy), hydroxy(C₁-C₆ alkyl), (C₁-C₆    alkoxy)C₁-C₆ alkyl, amino(C₁-C₆ alkyl), sulfanyl(C₁-C₆ alkyl), or    (C₁-C₆ alkyl)sulfanyl(C₁-C₆ alkyl);-   R₂ is C₁-C₆ alkyl, halo(C₁-C₆ alkyl), C₁-C₆ alkoxy, halo(C₁-C₆    alkoxy), hydroxy(C₁-C₆ alkyl), (C₁-C₆ alkoxy)C₁-C₆ alkyl,    formyl(C₀-C₆ alkyl), amino(C₁-C₆ alkyl), sulfanyl(C₁-C₆ alkyl),    (C₁-C₆ alkyl)sulfanyl(C₁-C₆ alkyl), —(CH₂)₁₋₅—C(O)OH,    —(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy), —(CH₂)₁₋₅—C(O)NH₂,    —(CH₂)₁₋₅—C(O)NH(C₁-C₆ alkyl), —(CH₂)₁₋₅—C(O)N(C₁-C₆ alkyl)₂,    —CH═CH—C(O)OH, —CH═CH—C(O)(C₁-C₆ alkoxy), (aryl)C₁-C₆ alkyl, or    (heteroaryl)C₁-C₆ alkyl; and-   R₆ is hydroxy, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆    alkoxy), benzyloxy, —(CH₂)₁₋₅—C(O)OH, —(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy),    —(CH₂)₁₋₅—C(O)NH₂, —(CH₂)₁₋₅—C(O)NH(C₁-C₆ alkyl),    —(CH₂)₁₋₅—C(O)N(C₁-C₆ alkyl)₂, —CH═CH—C(O)OH, —CH═CH—C(O)(C₁-C₆    alkoxy), —OS(O)₂CF₃, (aryl)C₁-C₆ alkyl, or (heteroaryl)C₁-C₆ alkyl.

The compounds of this first and second aspect of the invention have beenidentified as novel GPBP inhibitors. We have reported that GPBPself-interacts and that aggregation regulates kinase activity (WO00/50607). By combining a yeast two-hybrid system and cDNA deletionmutants of GPBP, we have identified a five-residue (SHCIE) (SEQ ID NO:1)motif in the GPBP amino acid sequence that is critical forself-interaction. A synthetic peptide representing the five-residuemotif and flanking regions (LATLSHCIELMVKR) (SEQ ID NO:2), referred toas Q₂, efficiently inhibited GPBP autophosphorylation and was shown toreduce α3(IV)NC1 conformer production by GPBP (see U.S. Pat. No.7,326,768, incorporated by reference herein in its entirety). Thecompounds of the present invention are peptidomimetics of the core ofthe self-interaction site of Q2 (SHCIE), and are shown herein to possessGPBP inhibitory activity, making them useful as therapeutics inantibody-mediated disorders, drug-resistant cancer, inflammation,protein misfolding and ER stress-mediated disorders, and aberrantapoptosis.

The invention also provides pharmaceutical compositions comprising acompound of this first or second aspect of the invention and at leastone pharmaceutically acceptable carrier, solvent, adjuvant or diluent.The compounds or pharmaceutical compositions of the invention can beprovided in a kit with instructions for using the compound orcomposition.

In a third aspect, the present invention provides methods for treatingantibody-mediated disorders, drug-resistant cancer, inflammation,protein misfolding and ER stress-mediated disorders, and aberrantapoptosis comprising administering one or more compounds orpharmaceutical compositions of the invention to a subject in needthereof.

DETAILED DESCRIPTION OF THE INVENTION

In one preferred embodiment, the compounds of formula (I) are of formula(II):

In another preferred embodiment, the disclosure provides compounds offormulae (I) or (II) wherein:

-   R is selected from N and CR₅;    -   R₅ is selected from the group consisting of hydrogen, halogen,        cyano, nitro, hydroxy, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, halo(C₁-C₆ alkyl), C₁-C₆ alkoxy, halo(C₁-C₆ alkoxy),        amino, (C₁-C₆ alkyl)amino, di(C₁-C₆ alkyl)amino, hydroxy(C₁-C₆        alkyl), (C₁-C₆ alkoxy)C₁-C₆ alkyl, amino(C₁-C₆ alkyl),        sulfanyl(C₁-C₆ alkyl), (C₁-C₆ alkyl)sulfanyl(C₁-C₆ alkyl),        —(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy), and —(CH₂)₁₋₅—C(O)NH₂;-   R₁ is hydrogen, halogen, hydroxy, C₁-C₆ alkyl, halo(C₁-C₆ alkyl),    C₁-C₆ alkoxy, halo(C₁-C₆ alkoxy), hydroxy(C₁-C₆ alkyl), (C₁-C₆    alkoxy)C₁-C₆ alkyl, amino(C₁-C₆ alkyl), sulfanyl(C₁-C₆ alkyl), or    (C₁-C₆ alkyl)sulfanyl(C₁-C₆ alkyl);-   R₂ is C₁-C₆ alkyl, halo(C₁-C₆ alkyl), C₁-C₆ alkoxy, halo(C₁-C₆    alkoxy), hydroxy(C₁-C₆ alkyl), (C₁-C₆ alkoxy)C₁-C₆ alkyl,    formyl(C₀-C₆ alkyl), amino(C₁-C₆ alkyl), sulfanyl(C₁-C₆ alkyl),    (C₁-C₆ alkyl)sulfanyl(C₁-C₆ alkyl), —(CH₂)₁₋₅—C(O)OH,    —(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy), or —(CH₂)₁₋₅—C(O)NH₂;-   R₃ is C₁-C₆ alkyl, halo(C₁-C₆ alkyl), C₁-C₆ alkoxy, halo(C₁-C₆    alkoxy), hydroxy(C₁-C₆ alkyl), (C₁-C₆ alkoxy)C₁-C₆ alkyl,    formyl(C₁-C₆ alkyl), amino(C₁-C₆ alkyl), sulfanyl(C₁-C₆ alkyl),    (C₁-C₆ alkyl)sulfanyl(C₁-C₆ alkyl), —(CH₂)₁₋₅—C(O)OH,    —(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy), —(CH₂)₁₋₅—C(O)NH₂,    —(CH₂)₁₋₅—C(O)NH(C₁-C₆ alkyl), —(CH₂)₁₋₅—C(O)N(C₁-C₆ alkyl)₂,    —CH═CH—C(O)OH, or —CH═CH—C(O)(C₁-C₆ alkoxy); and-   R₄ is hydroxy, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆    alkoxy), benzyloxy, —(CH₂)₁₋₅—C(O)OH, —(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy),    —(CH₂)₁₋₅—C(O)NH₂, —(CH₂)₁₋₅—C(O)NH(C₁-C₆ alkyl),    —(CH₂)₁₋₅—C(O)N(C₁-C₆ alkyl)₂, —CH═CH—C(O)OH, —CH═CH—C(O)(C₁-C₆    alkoxy), —O(CH₂)₁₋₅—C(O)OH, or —O(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy).

In another preferred embodiment, the disclosure provides compounds offormulae (I) or (II) wherein:

-   R is selected from N and CR₅;    -   R₅ is selected from the group consisting of hydrogen, halogen,        cyano, nitro, hydroxy, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, halo(C₁-C₆ alkyl), C₁-C₆ alkoxy, halo(C₁-C₆ alkoxy),        amino, (C₁-C₆ alkyl)amino, di(C₁-C₆ alkyl)amino, hydroxy(C₁-C₆        alkyl), (C₁-C₆ alkoxy)C₁-C₆ alkyl, and amino(C₁-C₆ alkyl);-   R₁ is hydrogen, halogen, hydroxy, C₁-C₆ alkyl, halo(C₁-C₆ alkyl),    C₁-C₆ alkoxy, or halo(C₁-C₆ alkoxy);-   R₂ is C₁-C₆ alkyl, halo(C₁-C₆ alkyl), hydroxy(C₁-C₆ alkyl), (C₁-C₆    alkoxy)C₁-C₆ alkyl, formyl(C₀-C₆ alkyl), amino(C₁-C₆ alkyl),    sulfanyl(C₁-C₆ alkyl), or (C₁-C₆ alkyl)sulfanyl(C₁-C₆ alkyl);-   R₃ is C₁-C₆ alkyl, —(CH₂)₁₋₅—C(O)OH, —(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy),    —(CH₂)₁₋₅—C(O)NH₂, —(CH₂)₁₋₅—C(O)NH(C₁-C₆ alkyl),    —(CH₂)₁₋₅—C(O)N(C₁-C₆ alkyl)₂, —CH═CH—C(O)OH, or —CH═CH—C(O)(C₁-C₆    alkoxy); and-   R₄ is hydroxy, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆    alkoxy), benzyloxy, —(CH₂)₁₋₅—C(O)OH, —(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy),    —(CH₂)₁₋₅—C(O)NH₂, —(CH₂)₁₋₅—C(O)NH(C₁-C₆ alkyl),    —(CH₂)₁₋₅—C(O)N(C₁-C₆ alkyl)₂, —CH═CH—C(O)OH, —CH═CH—C(O)(C₁-C₆    alkoxy), —O(CH₂)₁₋₅—C(O)OH, or —O(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy).

In another preferred embodiment, the disclosure provides compounds offormula (II), wherein R is N. These compounds can be represented byformula (III):

In yet another preferred embodiment, the disclosure provides compoundsof formula (II), wherein R is CR₅. These compounds can be represented byformula (IV):

In one preferred embodiment, the disclosure provides compounds asdescribed above with reference to any of formulae (I)-(IV), wherein R₁is hydrogen, hydroxy, or C₁-C₆ alkoxy.

In one preferred embodiment, the disclosure provides compounds asdescribed above with reference to any of formulae (I)-(IV), wherein R₁is hydrogen.

In another preferred embodiment, the disclosure provides compounds asdescribed above with reference to any of formulae (I)-(IV), wherein R₂is C₁-C₆ alkyl, halo(C₁-C₆ alkyl), hydroxy(C₁-C₆ alkyl), formyl(C₀-C₆alkyl), amino(C₁-C₆ alkyl), or sulfanyl(C₁-C₆ alkyl).

In yet another preferred embodiment, the disclosure provides compoundsas described above with reference to any of formulae (I)-(IV), whereinR₂ is C₁-C₆ alkyl, halo(C₁-C₆ alkyl), hydroxy(C₁-C₆ alkyl), orformyl(C₀-C₆ alkyl).

In yet another preferred embodiment, the disclosure provides compoundsas described above with reference to any of formulae (I)-(IV), whereinR₂ can be C₁-C₆ alkyl, halo(C₁-C₆ alkyl), or hydroxy(C₁-C₆ alkyl). Forexample, in certain embodiments R₂ can be C₁-C₆ alkyl such as methyl,ethyl, or isopropyl. In other embodiments, R₂ can be halo(C₁-C₆ alkyl)such as fluoromethyl, difluoromethyl, or trifluoromethyl. R₂ can, incertain embodiments, be hydroxy(C₁-C₆ alkyl). For example, thehydroxy(C₁-C₆ alkyl) can be hydroxymethyl, 1-hydroxyethyl, or2-hydroxyethyl.

In another preferred embodiment, the disclosure provides compounds asdescribed above with reference to any of formulae (I)-(IV), wherein R₂is C₁-C₆ alkyl. In certain preferred embodiments R₂ is methyl.

In another preferred embodiment, the disclosure provides compounds asdescribed above with reference to any of formulae (I)-(IV), wherein R₃is C₁-C₆ alkyl, —(CH₂)₁₋₅—C(O)OH, —(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy),—CH═CH—C(O)OH, or —CH═CH—C(O)(C₁-C₆ alkoxy).

In another preferred embodiment, the disclosure provides compounds asdescribed above with reference to any of formulae (I)-(IV), wherein R₃is —(CH₂)₁₋₅—C(O)OH, —(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy), or —(CH₂)₁₋₅—C(O)NH₂.

In yet another preferred embodiment, the disclosure provides compoundsas described above with reference to any of formulae (I)-(IV), whereinR₃ is —(CH₂)₁₋₂—C(O)OH, or —(CH₂)₁₋₂—C(O)(C₁-C₆ alkoxy). For example, incertain embodiments R₃ can be —(CH₂)₂—C(O)OH, —(CH₂)₂—C(O)(OCH₃),—(CH₂)₂—C(O)(OCH₂CH₃), or —(CH₂)₂—C(O)(OC(CH₃)₃). In other embodiments,R₃ can be —(CH₂)₂—C(O)OH, or —(CH₂)₂—C(O)(OCH₂CH₃).

In another preferred embodiment, the disclosure provides compounds asdescribed above with reference to any of formulae (I)-(IV), wherein R₃is —(CH₂)₁₋₂—C(O)OH. Preferrably R₃ is —(CH₂)₂—C(O)OH.

In one preferred embodiment, the disclosure provides compounds asdescribed above with reference to any of formulae (I)-(IV), wherein R₄is hydroxy, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆ alkoxy), orbenzyloxy.

In another preferred embodiment, the disclosure provides compounds asdescribed above with reference to any of formulae (I)-(IV), wherein R₄is hydroxy or C₁-C₆ alkoxy (e.g., methoxy). Preferrably R₄ is C₁-C₆alkoxy. In more preferred embodiment, R₄ is methoxy.

In one preferred embodiment, the disclosure provides compounds asdescribed above with reference to formulae (I), (II), or (IV), whereinR₅ is C₁-C₆ alkyl, halo(C₁-C₆ alkyl), C₁-C₆ alkoxy, or halo(C₁-C₆alkoxy).

In another preferred embodiment, the disclosure provides compounds asdescribed above with reference to formulae (I), (II), or (IV), whereinR₅ is C₁-C₆ alkyl, such as methyl.

In yet another preferred embodiment, the disclosure provides compoundsas described above with reference to formulae (I), (II), or (IV),wherein R₅ is halo(C₁-C₆ alkyl), such as trifluoromethyl.

In certain preferred embodiments, the disclosure provides compounds ofany of formulae (I), (II), or (IV), wherein:

-   -   R₅ is selected from the group consisting of hydrogen, halogen,        cyano, nitro, hydroxy, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, halo(C₁-C₆ alkyl), C₁-C₆ alkoxy, halo(C₁-C₆ alkoxy),        amino, (C₁-C₆ alkyl)amino, di(C₁-C₆ alkyl)amino, hydroxy(C₁-C₆        alkyl), (C₁-C₆ alkoxy)C₁-C₆ alkyl, and amino(C₁-C₆ alkyl);

-   R₁ is hydrogen, halogen, hydroxy, C₁-C₆ alkyl, halo(C₁-C₆ alkyl),    C₁-C₆ alkoxy, or halo(C₁-C₆ alkoxy);

-   R₂ is C₁-C₆ alkyl, halo(C₁-C₆ alkyl), hydroxy(C₁-C₆ alkyl), (C₁-C₆    alkoxy)C₁-C₆ alkyl, formyl(C₀-C₆ alkyl), amino(C₁-C₆ alkyl),    sulfanyl(C₁-C₆ alkyl), or (C₁-C₆ alkyl)thio(C₁-C₆ alkyl);

-   R₃ is —(CH₂)₁₋₂—C(O)OH, —(CH₂)₁₋₂—C(O)(C₁-C₆ alkoxy),    —(CH₂)₁₋₂—C(O)NH₂, —(CH₂)₁₋₂—C(O)NH(C₁-C₆ alkyl),    —(CH₂)₁₋₂—C(O)N(C₁-C₆ alkyl)₂, —CH═CH—C(O)OH, —CH═CH—C(O)(C₁-C₆    alkoxy); and

-   R₄ is hydroxy, C₁-C₆ alkoxy, halo(C₁-C₆ alkoxy), or benzyloxy.

In certain preferred embodiments, the disclosure provides compounds ofany of formula (III), wherein:

-   R₁ is hydrogen, halogen, hydroxy, C₁-C₆ alkyl, halo(C₁-C₆ alkyl),    C₁-C₆ alkoxy, or halo(C₁-C₆ alkoxy);-   R₂ is C₁-C₆ alkyl, halo(C₁-C₆ alkyl), hydroxy(C₁-C₆ alkyl), (C₁-C₆    alkoxy)C₁-C₆ alkyl, formyl(C₀-C₆ alkyl), amino(C₁-C₆ alkyl),    sulfanyl(C₁-C₆ alkyl), or (C₁-C₆ alkyl)thio(C₁-C₆ alkyl);-   R₃ is —(CH₂)₁₋₂—C(O)OH, —(CH₂)₁₋₂—C(O)(C₁-C₆ alkoxy),    —(CH₂)₁₋₂—C(O)NH₂, —(CH₂)₁₋₂—C(O)NH(C₁-C₆ alkyl),    —(CH₂)₁₋₂—C(O)N(C₁-C₆ alkyl)₂, —CH═CH—C(O)OH, —CH═CH—C(O)(C₁-C₆    alkoxy); and-   R₄ is hydroxy, C₁-C₆ alkoxy, halo(C₁-C₆ alkoxy), or benzyloxy.

In certain preferred embodiments, the disclosure provides compounds ofany of formulae (I), (II), or (IV), wherein R₁ is hydrogen; R₂ is C₁-C₆alkyl, halo(C₁-C₆ alkyl), hydroxy(C₁-C₆ alkyl), or formyl(C₁-C₆ alkyl);R₃ is —(CH₂)₁₋₂—C(O)OH, —(CH₂)₁₋₂—C(O)(C₁-C₆ alkoxy), or—(CH₂)₁₋₂—C(O)NH₂; R₄ is hydroxy or C₁-C₆ alkoxy; and R₅ is C₁-C₆ alkyl,halo(C₁-C₆ alkyl), C₁-C₆ alkoxy, or halo(C₁-C₆ alkoxy).

In certain preferred embodiments, the disclosure provides compounds ofany of formula (III), wherein R₁ is hydrogen; R₂ is C₁-C₆ alkyl,halo(C₁-C₆ alkyl), hydroxy(C₁-C₆ alkyl), or formyl(C₁-C₆ alkyl); R₃ is—(CH₂)₁₋₂—C(O)OH, —(CH₂)₁₋₂—C(O)(C₁-C₆ alkoxy), or —(CH₂)₁₋₂—C(O)NH₂; R₄is hydroxy or C₁-C₆ alkoxy; and R₅ is C₁-C₆ alkyl, halo(C₁-C₆ alkyl),C₁-C₆ alkoxy, or halo(C₁-C₆ alkoxy).

In certain preferred embodiments, the disclosure provides compounds ofany of formulae (I)-(IV), wherein:

-   R, if present, is selected from N and CR₅;    -   R₅ is selected from the group consisting of hydrogen, halogen,        cyano, nitro, hydroxy, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, halo(C₁-C₆ alkyl), C₁-C₆ alkoxy, halo(C₁-C₆ alkoxy),        amino, (C₁-C₆ alkyl)amino, di(C₁-C₆ alkyl)amino, hydroxy(C₁-C₆        alkyl), (C₁-C₆ alkoxy)C₁-C₆ alkyl, and amino(C₁-C₆ alkyl);-   R₁ is hydrogen;-   R₂ is C₁-C₆ alkyl;-   R₃ is —(CH₂)₁₋₂—C(P)OH; and-   R₄ is C₁-C₆ alkoxy.

In certain preferred embodiments, the disclosure provides compounds ofany of formulae (I)-(IV), wherein:

-   R, if present, is selected from N and CR₅;    -   R₅ is selected from the group consisting of hydrogen, halogen,        cyano, nitro, hydroxy, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, halo(C₁-C₆ alkyl), C₁-C₆ alkoxy, halo(C₁-C₆ alkoxy),        amino, (C₁-C₆ alkyl)amino, di(C₁-C₆ alkyl)amino, hydroxy(C₁-C₆        alkyl), (C₁-C₆ alkoxy)C₁-C₆ alkyl, and amino(C₁-C₆ alkyl);-   R₁ is hydrogen;-   R₂ is methyl;-   R₃ is —(CH₂)₂—C(O)OH; and-   R₄ is methoxy.

In one preferred embodiment, the compounds of formula (V) are of formula(VI):

In another preferred embodiment, the disclosure provides compounds offormulae (V) or (VI) wherein:

-   R is selected from N and CR₅;    -   R₅ is selected from the group consisting of hydrogen, halogen,        cyano, nitro, hydroxy, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, halo(C₁-C₆ alkyl), C₁-C₆ alkoxy, halo(C₁-C₆ alkoxy),        amino, (C₁-C₆ alkyl)amino, di(C₁-C₆ alkyl)amino, hydroxy(C₁-C₆        alkyl), (C₁-C₆ alkoxy)C₁-C₆ alkyl, amino(C₁-C₆ alkyl),        sulfanyl(C₁-C₆ alkyl), (C₁-C₆ alkyl)sulfanyl(C₁-C₆ alkyl),        —(CH₂)₁₋₅—C(O)OH, —(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy), and        —(CH₂)₁₋₅—C(O)NH₂;-   R₁ is hydrogen, halogen, hydroxy, C₁-C₆ alkyl, halo(C₁-C₆ alkyl),    C₁-C₆ alkoxy, halo(C₁-C₆ alkoxy), hydroxy(C₁-C₆ alkyl), (C₁-C₆    alkoxy)C₁-C₆ alkyl, amino(C₁-C₆ alkyl), sulfanyl(C₁-C₆ alkyl), or    (C₁-C₆ alkyl)sulfanyl(C₁-C₆ alkyl);-   R₂ is C₁-C₆ alkyl, halo(C₁-C₆ alkyl), C₁-C₆ alkoxy, halo(C₁-C₆    alkoxy), hydroxy(C₁-C₆ alkyl), (C₁-C₆ alkoxy)C₁-C₆ alkyl,    formyl(C₀-C₆ alkyl), amino(C₁-C₆ alkyl), sulfanyl(C₁-C₆ alkyl),    (C₁-C₆ alkyl)sulfanyl(C₁-C₆ alkyl), —(CH₂)₁₋₅—C(O)OH,    —(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy), —(CH₂)₁₋₅—C(O)NH₂, —CH═CH—C(O)OH, or    —CH═CH—C(O)(C₁-C₆ alkoxy); and-   R₆ is hydroxy, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆    alkoxy), benzyloxy, —(CH₂)₁₋₅—C(O)OH, —(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy),    —(CH₂)₁₋₅—C(O)NH₂, —(CH₂)₁₋₅—C(O)NH(C₁-C₆ alkyl),    —(CH₂)₁₋₅—C(O)N(C₁-C₆ alkyl)₂, —CH═CH—C(O)OH, —CH═CH—C(O)(C₁-C₆    alkoxy), or —OS(O)₂CF₃.

In another preferred embodiment, the disclosure provides compounds offormulae (V) or (VI) wherein:

-   R is selected from N and CR₅;    -   R₅ is selected from the group consisting of hydrogen, halogen,        cyano, nitro, hydroxy, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, halo(C₁-C₆ alkyl), C₁-C₆ alkoxy, halo(C₁-C₆ alkoxy),        amino, (C₁-C₆ alkyl)amino, di(C₁-C₆ alkyl)amino, hydroxy(C₁-C₆        alkyl), (C₁-C₆ alkoxy)C₁-C₆ alkyl, and amino(C₁-C₆ alkyl);-   R₁ is hydrogen, halogen, hydroxy, C₁-C₆ alkyl, halo(C₁-C₆ alkyl),    C₁-C₆ alkoxy, or halo(C₁-C₆ alkoxy);-   R₂ is C₁-C₆ alkyl, halo(C₁-C₆ alkyl), hydroxy(C₁-C₆ alkyl), (C₁-C₆    alkoxy)C₁-C₆ alkyl, formyl(C₀-C₆ alkyl), amino(C₁-C₆ alkyl),    sulfanyl(C₁-C₆ alkyl), (C₁-C₆ alkyl)sulfanyl(C₁-C₆ alkyl),    —CH═CH—C(O)OH, or —CH═CH—C(O)(C₁-C₆ alkoxy); and-   R₆ is hydroxy, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆    alkoxy), benzyloxy, —(CH₂)₁₋₅—C(O)OH, —(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy),    —(CH₂)₁₋₅—C(O)NH₂, —(CH₂)₁₋₅—C(O)NH(C₁-C₆ alkyl),    —(CH₂)₁₋₅—C(O)N(C₁-C₆ alkyl)₂, —CH═CH—C(O)OH, —CH═CH—C(O)(C₁-C₆    alkoxy), or —OS(O)₂CF₃.

In one preferred embodiment, the disclosure provides compounds asdescribed above with reference to any of formulae (V)-(VI), wherein R₁is hydrogen.

In another preferred embodiment, the disclosure provides compounds asdescribed above with reference to any of formulae (V)-(VI), wherein R₂is C₁-C₆ alkyl, halo(C₁-C₆ alkyl), hydroxy(C₁-C₆ alkyl), formyl(C₀-C₆alkyl), amino(C₁-C₆ alkyl), sulfanyl(C₁-C₆ alkyl), —CH═CH—C(O)OH, or—CH═CH—C(O)(C₁-C₆ alkoxy).

In yet another preferred embodiment, the disclosure provides compoundsas described above with reference to any of formulae (V)-(VI), whereinR₂ is C₁-C₆ alkyl, halo(C₁-C₆ alkyl), hydroxy(C₁-C₆ alkyl), formyl(C₀-C₆alkyl), —CH═CH—C(O)OH, or —CH═CH—C(O)(C₁-C₆ alkoxy).

In yet another preferred embodiment, the disclosure provides compoundsas described above with reference to any of formulae (V)-(VI), whereinR₂ can be C₁-C₆ alkyl, halo(C₁-C₆ alkyl), hydroxy(C₁-C₆ alkyl), or—CH═CH—C(O)(C₁-C₆ alkoxy). For example, in certain embodiments R₂ can beC₁-C₆ alkyl such as methyl, ethyl, or isopropyl. In other embodiments,R₂ can be halo(C₁-C₆ alkyl) such as fluoromethyl, difluoromethyl, ortrifluoromethyl. R₂ can, in certain embodiments, be hydroxy(C₁-C₆alkyl). For example, the hydroxy(C₁-C₆ alkyl) can be hydroxymethyl,1-hydroxyethyl, or 2-hydroxyethyl.

In another preferred embodiment, the disclosure provides compounds asdescribed above with reference to any of formulae (V)-(VI), wherein R₂is C₁-C₆ alkyl. In certain preferred embodiments R₂ is methyl.

In one preferred embodiment, the disclosure provides compounds asdescribed above with reference to any of formulae (V)-(VI), wherein R₆is hydroxy, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆ alkoxy),benzyloxy, or —OS(O)₂CF₃.

In another preferred embodiment, the disclosure provides compounds asdescribed above with reference to any of formulae (V)-(VI), wherein R₆is hydroxy or C₁-C₆ alkoxy (e.g., methoxy).

In one preferred embodiment, the disclosure provides compounds asdescribed above with reference to formulae (V)-(VI), wherein R₅ is C₁-C₆alkyl, halo(C₁-C₆ alkyl), C₁-C₆ alkoxy, or halo(C₁-C₆ alkoxy).

In another preferred embodiment, the disclosure provides compounds asdescribed above with reference to formulae (V)-(VI), wherein R₅ is C₁-C₆alkyl, such as methyl.

In yet another preferred embodiment, the disclosure provides compoundsas described above with reference to formulae (V)-(VI), wherein R₅ ishalo(C₁-C₆ alkyl), such as trifluoromethyl.

In certain preferred embodiments, the disclosure provides compounds ofany of formulae (V)-(VI), wherein:

-   -   R₅ is selected from the group consisting of hydrogen, halogen,        cyano, nitro, hydroxy, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, halo(C₁-C₆ alkyl), C₁-C₆ alkoxy, halo(C₁-C₆ alkoxy),        amino, (C₁-C₆ alkyl)amino, di(C₁-C₆ alkyl)amino, hydroxy(C₁-C₆        alkyl), (C₁-C₆ alkoxy)C₁-C₆ alkyl, and amino(C₁-C₆ alkyl);

-   R₁ is hydrogen, halogen, hydroxy, C₁-C₆ alkyl, halo(C₁-C₆ alkyl),    C₁-C₆ alkoxy, or halo(C₁-C₆ alkoxy);

-   R₂ is C₁-C₆ alkyl, halo(C₁-C₆ alkyl), hydroxy(C₁-C₆ alkyl), (C₁-C₆    alkoxy)C₁-C₆ alkyl, formyl(C₀-C₆ alkyl), amino(C₁-C₆ alkyl),    sulfanyl(C₁-C₆ alkyl), (C₁-C₆ alkyl)thio(C₁-C₆ alkyl), or    —CH═CH—C(O)(C₁-C₆ alkoxy); and

-   R₆ is hydroxy, C₁-C₆ alkoxy, halo(C₁-C₆ alkoxy), or —OS(O)₂CF₃.

In certain preferred embodiments, the disclosure provides compounds ofany of formulae (V)-(VI), wherein R₁ is hydrogen; R₂ is C₁-C₆ alkyl,halo(C₁-C₆ alkyl), hydroxy(C₁-C₆ alkyl), formyl(C₀-C₆ alkyl), or—CH═CH—C(O)(C₁-C₆ alkoxy); R₆ is hydroxy, C₁-C₆ alkoxy, or —OS(O)₂CF₃;and R₅ is C₁-C₆ alkyl, halo(C₁-C₆ alkyl), C₁-C₆ alkoxy, or halo(C₁-C₆alkoxy).

The compounds of the invention include pharmaceutically acceptablesalts, esters, amides, and prodrugs thereof, including but not limitedto carboxylate salts, amino acid addition salts, esters, amides, andprodrugs of the compounds of the present invention which are, within thescope of sound medical judgment, suitable for use in contact with thetissues of patients without undue toxicity, irritation, allergicresponse, and the like, commensurate with a reasonable benefit/riskratio, and effective for their intended use, as well as the zwitterionicforms, where possible, of the compounds of the invention. The term“salts” refers to the relatively non-toxic, inorganic and organic acidaddition salts of compounds of the present invention. These salts can beprepared in situ during the final isolation and purification of thecompounds or by separately reacting the purified compound in its freebase form with a suitable organic or inorganic acid and isolating thesalt thus formed. Representative salts include the hydrobromide,hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate,oleate, palmitate, stearate, laurate, borate, benzoate, lactate,phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate,naphthylate, mesylate, glucoheptonate, lactobionate, andlaurylsulphonate salts, and the like. These may include cations based onthe alkali and alkaline earth metals, such as sodium, lithium,potassium, calcium, magnesium, and the like, as well as non-toxicammonium, quaternary ammonium, and amine cations including, but notlimited to ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine,and the like. (See, for example, Berge S. M. et al., “PharmaceuticalSalts,” J. Pharm. Sci., 1977; 66:1-19 which is incorporated herein byreference.)

Examples of pharmaceutically acceptable, non-toxic esters of thecompounds of this invention include C₁-C₆ alkyl esters, wherein thealkyl group is a straight or branched, substituted or unsubstituted,C₅-C₇ cycloalkyl esters, as well as arylalkyl esters such as benzyl andtriphenylmethyl. C₁-C₄ alkyl esters are preferred, such as methyl,ethyl, 2,2,2-trichloroethyl, and tert-butyl. Esters of the compounds ofthe present invention may be prepared according to conventional methods.

Examples of pharmaceutically acceptable, non-toxic amides of thecompounds of this invention include amides derived from ammonia, primaryC₁-C₆ alkyl amines and secondary C₁-C₆ dialkyl amines, wherein the alkylgroups are straight or branched. In the case of secondary amines, theamine may also be in the form of a 5- or 6-membered heterocyclecontaining one nitrogen atom. Amides derived from ammonia, C₁-C₃ alkylprimary amines and C₁-C₂ dialkyl secondary amines are preferred. Amidesof the compounds of the invention may be prepared according toconventional methods.

The term “prodrug” refers to compounds that are rapidly transformed invivo to yield the parent compound of the above formulae, for example, byhydrolysis in blood. A thorough discussion of prodrugs is provided in T.Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 ofthe A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are hereby incorporated byreference.

In one embodiment, the disclosure provides pharmaceutical compositionscomprising a compound as described above with reference to any one offormulae (I)-(VI) and at least one pharmaceutically acceptable carrier,solvent, adjuvant or diluent.

For administration, the compounds are ordinarily combined with one ormore adjuvants appropriate for the indicated route of administration.The compounds may be mixed with lactose, sucrose, starch powder,cellulose esters of alkanoic acids, stearic acid, talc, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulphuric acids, acacia, gelatin, sodium alginate, polyvinylpyrrolidine,and/or polyvinyl alcohol, and tableted or encapsulated for conventionaladministration. Alternatively, the compounds of this invention may bedissolved in saline, water, polyethylene glycol, propylene glycol,carboxymethyl cellulose colloidal solutions, ethanol, corn oil, peanutoil, cottonseed oil, sesame oil, tragacanth gum, and/or various buffers.Other adjuvants and modes of administration are well known in thepharmaceutical art. The carrier or diluent may include time delaymaterial, such as glyceryl monostearate or glyceryl distearate alone orwith a wax, or other materials well known in the art.

The compounds of the invention can be administered as the sole activepharmaceutical agent, or they can be used in combination with one ormore other compounds useful for carrying out the methods of theinvention. When administered as a combination, the therapeutic agentscan be formulated as separate compositions that are given at the sametime or different times, or the therapeutic agents can be given as asingle composition.

The compounds may be made up in a solid form (including granules,powders or suppositories) or in a liquid form (e.g., solutions,suspensions, or emulsions). The compounds of the invention may beapplied in a variety of solutions and may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containconventional adjuvants, such as preservatives, stabilizers, wettingagents, emulsifiers, buffers etc.

The compounds of the invention may be administered orally, topically,parenterally, by inhalation or spray or rectally in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes percutaneous, subcutaneous, intravascular (e.g.,intravenous), intramuscular, or intrathecal injection or infusiontechniques and the like. In addition, there is provided a pharmaceuticalformulation comprising a compound of the invention and apharmaceutically acceptable carrier. One or more compounds of theinvention may be present in association with one or more non-toxicpharmaceutically acceptable carriers and/or diluents and/or adjuvants,and if desired other active ingredients. The pharmaceutical compositionscontaining compounds of the invention may be in a form suitable for oraluse, for example, as tablets, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsion, hard or softcapsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preservative agents in order to providepalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients that aresuitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques. Insome cases such coatings may be prepared by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monosterate or glyceryl distearate maybe employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents and flavoring agents may beadded to provide palatable oral preparations. These compositions may bepreserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents orsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil or amineral oil or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol, glucose or sucrose. Suchformulations may also contain a demulcent, a preservative, and flavoringand coloring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleaginous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents that havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxic parentallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds and pharmaceutical compositions of the present inventionmay also be administered in the form of suppositories, e.g., for rectaladministration of the drug. These compositions can be prepared by mixingthe drug with a suitable non-irritating excipient that is solid atordinary temperatures but liquid at the rectal temperature and willtherefore melt in the rectum to release the drug. Such materials includecocoa butter and polyethylene glycols.

Compounds and pharmaceutical compositions of the present invention maybe administered parenterally in a sterile medium. The drug, depending onthe vehicle and concentration used, can either be suspended or dissolvedin the vehicle. Advantageously, adjuvants such as local anesthetics,preservatives and buffering agents can be dissolved in the vehicle.

In a third aspect, the present invention provides methods for treatingantibody-mediated disorders, drug-resistant cancer, inflammation,protein misfolding and ER stress-mediated disorders, and aberrantapoptosis comprising administering an amount effective of one or morecompounds or pharmaceutical compositions of the invention to a subjectin need thereof to treat the antibody-mediated disorder, drug-resistantcancer, inflammation, protein misfolding and ER stress-mediateddisorder, or aberrant apoptosis. As used herein, the antibody-mediateddisorders may comprise any immune-complex and autoimmune mediateddisorder, such as a glomerulonephritis selected from the groupconsisting of IgA nephropathy, systemic lupus erythematosus andGoodpasture syndrome.

As used herein, “treat” or “treating” means accomplishing one or more ofthe following: (a) reducing the severity of the disorder; (b) limitingor preventing development of symptoms characteristic of the disorder(s)being treated; (c) inhibiting worsening of symptoms characteristic ofthe disorder(s) being treated; (d) limiting or preventing recurrence ofthe disorder(s) in patients that have previously had the disorder(s);and (e) limiting or preventing recurrence of symptoms in patients thatwere previously symptomatic for the disorder(s).

Dosage levels of the order of from about 0.01 mg to about 50 mg perkilogram of body weight per day, and more preferably between 0.1 mg toabout 50 mg per kilogram of body weight per day, are useful in thetreatment of the above-indicated conditions. The amount of activeingredient that may be combined with the carrier materials to produce asingle dosage form will vary depending upon the host treated and theparticular mode of administration. Dosage unit forms will generallycontain between from about 1 mg to about 500 mg of an active ingredient.

Compounds or pharmaceutical compositions containing the compoundsdescribed herein are administered to an individual in need thereof. In apreferred embodiment, the subject is a mammal; in a more preferredembodiment, the subject is a human. In therapeutic applications,compositions are administered in an amount sufficient to carry out themethods of the invention. Amounts effective for these uses depend onfactors including, but not limited to, the nature of the compound(specific activity, etc.), the route of administration, the stage andseverity of the disorder, the weight and general state of health of thesubject, and the judgment of the prescribing physician. The activecompounds are effective over a wide dosage range. However, it will beunderstood that the amount of the compound actually administered will bedetermined by a physician, in the light of the above relevantcircumstances. Therefore, the above dosage ranges are not intended tolimit the scope of the invention in any way.

Definitions

The term “alkenyl” as used herein, means a straight or branched chainhydrocarbon containing from 2 to 10 carbons, unless otherwise specified,and containing at least one carbon-carbon double bond. Representativeexamples of alkenyl include, but are not limited to, ethenyl,2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl,2-heptenyl, 2-methyl-1-heptenyl, 3-decenyl, and3,7-dimethylocta-2,6-dienyl.

The term “alkoxy” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkyl” as used herein, means a straight or branched chainhydrocarbon containing from 1 to 10 carbon atoms unless otherwisespecified. Representative examples of alkyl include, but are not limitedto, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl. When an “alkyl” group is a linking group between two othermoieties, then it may also be a straight or branched chain; examplesinclude, but are not limited to —CH₂—, —CH₂CH₂—, —CH₂CH₂CHC(CH₃)—,—CH₂CH(CH₂CH₃)CH₂—.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from one to six, from one to four, from oneto three, from one to two, or from two to three. A substituted alkylenechain is a polymethylene group in which one or more methylene hydrogenatoms is replaced with a substituent. Suitable substituents includethose described below for a substituted aliphatic group. An alkylenechain also may be substituted at one or more positions with an aliphaticgroup or a substituted aliphatic group.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,3-butynyl, 2-pentynyl, and 1-butynyl.

The term “aryl,” as used herein, means a phenyl (i.e., monocyclic aryl),or a bicyclic ring system containing at least one phenyl ring or anaromatic bicyclic ring containing only carbon atoms in the aromaticbicyclic ring system. The bicyclic aryl can be azulenyl, naphthyl, or aphenyl fused to a monocyclic cycloalkyl, a monocyclic cycloalkenyl, or amonocyclic heterocyclyl. The bicyclic aryl is attached to the parentmolecular moiety through any carbon atom contained within the phenylportion of the bicyclic system, or any carbon atom with the napthyl orazulenyl ring. The fused monocyclic cycloalkyl or monocyclicheterocyclyl portions of the bicyclic aryl are optionally substitutedwith one or two oxo and/or thia groups. Representative examples of thebicyclic aryls include, but are not limited to, azulenyl, naphthyl,dihydroinden-1-yl, dihydroinden-2-yl, dihydroinden-3-yl,dihydroinden-4-yl, 2,3-dihydroindol-4-yl, 2,3-dihydroindol-5-yl,2,3-dihydroindol-6-yl, 2,3-dihydroindol-7-yl, inden-1-yl, inden-2-yl,inden-3-yl, inden-4-yl, dihydronaphthalen-2-yl, dihydronaphthalen-3-yl,dihydronaphthalen-4-yl, dihydronaphthalen-1-yl,5,6,7,8-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl,2,3-dihydrobenzofuran-4-yl, 2,3-dihydrobenzofuran-5-yl,2,3-dihydrobenzofuran-6-yl, 2,3-dihydrobenzofuran-7-yl,benzo[d][1,3]dioxol-4-yl, benzo[d][1,3]dioxol-5-yl,2H-chromen-2-on-5-yl, 2H-chromen-2-on-6-yl, 2H-chromen-2-on-7-yl,2H-chromen-2-on-8-yl, isoindoline-1,3-dion-4-yl,isoindoline-1,3-dion-5-yl, inden-1-on-4-yl, inden-1-on-5-yl,inden-1-on-6-yl, inden-1-on-7-yl, 2,3-dihydrobenzo[b][1,4]dioxan-5-yl,2,3-dihydrobenzo[b][1,4]dioxan-6-yl,2H-benzo[b][1,4]oxazin3(4H)-on-5-yl,2H-benzo[b][1,4]oxazin3(4H)-on-6-yl,2H-benzo[b][1,4]oxazin3(4H)-on-7-yl,2H-benzo[b][1,4]oxazin3(4H)-on-8-yl, benzo[d]oxazin-2(3H)-on-5-yl,benzo[d]oxazin-2(3H)-on-6-yl, benzo[d]oxazin-2(3H)-on-7-yl,benzo[d]oxazin-2(3H)-on-8-yl, quinazolin-4(3H)-on-5-yl,quinazolin-4(3H)-on-6-yl, quinazolin-4(3H)-on-7-yl,quinazolin-4(3H)-on-8-yl, quinoxalin-2(1H)-on-5-yl,quinoxalin-2(1H)-on-6-yl, quinoxalin-2(1H)-on-7-yl,quinoxalin-2(1H)-on-8-yl, benzo[d]thiazol-2(3H)-on-4-yl,benzo[d]thiazol-2(3H)-on-5-yl, benzo[d]thiazol-2(3H)-on-6-yl, and,benzo[d]thiazol-2(3H)-on-7-yl. In certain embodiments, the bicyclic arylis (i) naphthyl or (ii) a phenyl ring fused to either a 5 or 6 memberedmonocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, or a 5or 6 membered monocyclic heterocyclyl, wherein the fused cycloalkyl,cycloalkenyl, and heterocyclyl groups are optionally substituted withone or two groups which are independently oxo or thia.

The term “halo” or “halogen” as used herein, means —Cl, —Br, —I or —F.

The terms “haloalkyl”, “haloalkenyl” and “haloalkoxy” refer to an alkyl,alkenyl or alkoxy group, as the case may be, which is substituted withone or more halogen atoms.

The term “heteroaryl,” as used herein, means a monocyclic heteroaryl ora bicyclic ring system containing at least one heteroaromatic ring. Themonocyclic heteroaryl can be a 5 or 6 membered ring. The 5 membered ringconsists of two double bonds and one, two, three or four nitrogen atomsand optionally one oxygen or sulfur atom. The 6 membered ring consistsof three double bonds and one, two, three or four nitrogen atoms. The 5or 6 membered heteroaryl is connected to the parent molecular moietythrough any carbon atom or any nitrogen atom contained within theheteroaryl. Representative examples of monocyclic heteroaryl include,but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl,triazolyl, and triazinyl. The bicyclic heteroaryl consists of amonocyclic heteroaryl fused to a phenyl, a monocyclic cycloalkyl, amonocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclicheteroaryl. The fused cycloalkyl or heterocyclyl portion of the bicyclicheteroaryl group is optionally substituted with one or two groups whichare independently oxo or thia. When the bicyclic heteroaryl contains afused cycloalkyl, cycloalkenyl, or heterocyclyl ring, then the bicyclicheteroaryl group is connected to the parent molecular moiety through anycarbon or nitrogen atom contained within the monocyclic heteroarylportion of the bicyclic ring system. When the bicyclic heteroaryl is amonocyclic heteroaryl fused to a benzo ring, then the bicyclicheteroaryl group is connected to the parent molecular moiety through anycarbon atom or nitrogen atom within the bicyclic ring system.Representative examples of bicyclic heteroaryl include, but are notlimited to, benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl,benzoxathiadiazolyl, benzothiazolyl, cinnolinyl,5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-1-yl, furopyridinyl,indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, purinyl,5,6,7,8-tetrahydroquinolin-2-yl, 5,6,7,8-tetrahydroquinolin-3-yl,5,6,7,8-tetrahydroquinolin-4-yl, 5,6,7,8-tetrahydroisoquinolin-1-yl,thienopyridinyl, 4,5,6,7-tetrahydrobenzo[c][1,2,5]oxadiazolyl, and6,7-dihydrobenzo[c][1,2,5]oxadiazol-4(5H)-onyl. In certain embodiments,the fused bicyclic heteroaryl is a 5 or 6 membered monocyclic heteroarylring fused to either a phenyl ring, a 5 or 6 membered monocycliccycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 memberedmonocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl,wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups areoptionally substituted with one or two groups which are independentlyoxo or thia.

“Pharmaceutically acceptable” refers to those compounds, materials,compositions, and/or dosage forms which are, within the scope of soundmedical judgment, suitable for contact with the tissues of human beingsand animals without excessive toxicity, irritation, allergic response,or other problems or complications commensurate with a reasonablebenefit/risk ratio or which have otherwise been approved by the UnitedStates Food and Drug Administration as being acceptable for use inhumans or domestic animals.

The present invention may be better understood with reference to theaccompanying examples that are intended for purposes of illustrationonly and should not be construed to limit the scope of the invention.

EXAMPLES Synthesis of Q₂ Peptidomimetics

New terphenyl compounds capable of mimicking the peptide Q₂ (SEQ IDNO:2) (U.S. Pat. No. 7,326,768) and modulating the kinase activity ofGPBP are synthesized. Scheme 1 shows the terphenyl peptidomimeticproposed: every phenyl ring of this scaffold contains a different groupthat mimics the following amino acids:

a) alanine, serine and glutamic acid in the case of compound 1.

b) serine, glutamic acid and valine in the case of compound 2.

The synthetic strategy lies in a modular synthesis of3,2′,2″-tris-substituted-terphenyl derivatives by means of palladiumcatalysed cross coupling reactions between the different phenyl synthons(bromoaryls, aryltriflates, boronates and boronic acids).

Synthesis

In order to diversify and modify the solubility/lipophilicity of theterphenyl scaffold 1, the changes in the phenyl ring that mimics thealanine residue are introduced: a nitrogen atom and a trifluoromethylgroup increase the family of terphenyl 1 derivates (Scheme 2).

The first step of this synthesis consisted of the regioselectivebromination of commercial 3-hydroxybenzaldehyde in accordance with aknown procedure. The resulting bromoaryl 3 reacted with severaldifferent commercial boronic acids or boronates to afford biphenyls 4(Scheme 3).

In turn, phenols 4 were transformed into triflates 5 with triflicanhydride and pyridine as reagents. Triflates 5 reacted with boronate 6under Suzuki coupling conditions to give terphenyls 7 (Scheme 4).

Boronate 6 was previously synthesized from 2-bromo-5-hydroxybenzaldehyde3 (Scheme 5).

Catalytic hydrogenation of terphenyl intermediates 7 reduced the doublebound, cleaved the benzyl group and also reduced the carbonyl group tomethyl group to give compounds 11. Basic hydrolysis of ethyl estersprovided final terphenylic compounds 12 (Scheme 6).

Basic hydrolysis of esters 13 provided the terphenyl 1 compounds (Scheme7).

Direct fluorination of the hydroxyl group of terphenyls 13 was carriedout to afford the derivates 14. Basic hydrolysis of the ethyl esters 14gave the final fluorinated terphenyls 15 (Scheme 8).

Direct fluorination of the aldehyde group of terphenyls 7 was onlyachieved in compound 7c, so fluorination of the carbonyl group must becarried out with the biphenyls 4a,b. Difluorinated terphenyls 18a,b wereobtained. After catalytic hydrogenation, basic hydrolysis of ethylesters 19 gave the final difluorinated terphenyls 20 (Scheme 9).

Alkyl side chain modifications were performed in the phenolic positionof the terphenyl molecules to increase the family of compounds withoutchanges in the terphenyl residues (Scheme 10).

Iodination of commercial 3-(3-methoxyphenyl)propionic acid, followed bythe Miyaura boronation reaction afforded boronate 27 (Scheme 11).

Boronate 27 was coupled with triflate 5c to afford the terphenyl 28 withsimilar reaction conditions to those described above. After carbonylreduction and basic hydrolysis of the ethyl ester, compound 22i wasobtained (Scheme 12).

Terphenyl 22k was obtained from compound 21i after hydroxyl groupfluorination and basic hydrolysis of the ethyl ester (Scheme 13).

Direct fluorination of terphenyl 28 was achieved to give the compound22l (Scheme 14).

Finally, two more terphenylic compounds (22j and 32) were prepared withthe same methodology described above (Scheme 15).

Synthesis of the Second Terphenylic Family

After regioselective bromination of commercial 3-isopropylphenol,boronate 35 was obtained (Scheme 16).

This boronate was coupled with triflate 37 to afford the new terphenylderivate 38. Catalytic hydrogenation under high hydrogen pressure andPd(OH)₂ caused total reduction of the carbonyl group and served tosynthesize another terphenylic compound that could mimic alanine,glutamic acid and valine residues (Scheme 17).

Experimental Procedures

General Method: The reactions were carried out under nitrogen atmosphereunless otherwise indicated. CH₂Cl₂ was distilled from calcium hydrideprior to use. All other solvents and reagents were used as receivedunless otherwise stated. The reactions were monitored with the aid ofthin-layer chromatography (TLC) on 0.25 mm E. Merk precoated silica gelplates. Visualization was carried out with UV light, aqueous cericammonium molybdate solution or potassium permanganate stain. Flashcolumn chromatography was performed with the indicated solvents onsilica gel 60 (particle size 0.040-0.063 mm). All compounds arecolourless oils, if not otherwise stated. Melting points were measuredwith a “Büchi B-540” apparatus. ¹H, ¹³C, and ¹⁹F NMR spectra wererecorded on 300 MHz Bruker Advance spectrometer. Chemical shifts (6) aregiven in ppm. Coupling constants (J) are given in Hertz (Hz). Theletters m, s, d, t, and q stand for multiplet, singlet, doublet,triplet, and quartet, respectively. The letters br indicate that thesignal is broad. High-resolution mass spectra measurements were carriedout on a VGmAutospec instrument (VG Analytical, Micromass Instruments)by the Universitat de Valencia Mass Spectrometry Service.

Example 1 2-bromo-5-hydroxybenzaldehyde (3)

3-hydroxybenzaldehyde (10 g, 81.9 mmol) was dissolved in glacial aceticacid (50 mL) and cooled at 15° C. To the stirred solution, bromine (15.7g, 98.2 mmol) was added dropwise while keeping the temperature below 22°C. After overnight stirring at room temperature, the volatiles wereremoved under vacuum without heating; the residue was co-evaporatedthree times with hexane (15 mL) and taken up in warm chloroform. Uponcooling, 9.05 g of 2-bromo-5-hydroxybenzaldehyde 3 were obtained as awhite solid in two crops. Yield 55%. ¹H NMR (300 MHz, CD₃COCD₃) δ ppm:10.24 (s, 1H), 9.05 (s, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.34 (d, J=3.1 Hz,1H), 7.10 (dd, J₁=8.7 Hz, J₂=3.1 Hz, 1H); ¹³C NMR (75 MHz, CD₃COCD₃) δppm: 192.8, 159.3, 136.7, 136.2, 125.1, 117.3, 117.2; HRMS (EI) m/z:calcd for C₇H₅BrO₂: 199.9472. found: 199.9463; mp: 132-134° C.

General Procedure for the Synthesis of Biphenyls 4, 29 and 36

Bromoaryl (1 equiv), boronic acid or boronate (1.1 equiv), potassiumphosphate (3 equiv) and palladium tetrakistriphenylphosfine (0.02 equiv)were dissolved in acetonitrile/water (7:3) and the resulting mixture wasrefluxed for 4 h under inert atmosphere. The reaction mixture was pouredand aqueous layer was extracted with AcOEt. The combined organic layerswere dried over Na₂SO₄, filtered and removed in vacuo. The resultingcrude reaction product was purified by means of flash chromatography onsilica gel.

Example 2 4-hydroxy-3′-methylbiphenyl-2-carbaldehyde (4a)

Yield 80% (hexane/AcOEt 10:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 9.93 (s,1H), 7.52 (d, J=2.7 Hz, 1H), 7.63 (t, J=8.1 Hz, 2H), 7.24 (d, J=7.8 Hz,1H), 7.20-7.13 (m, 3H), 5.73 (s, 1H), 2.42 (s, 3H); ¹³C NMR (75 MHz,CDCl₃) δ ppm: 192.8, 155.3, 139.3, 138.1, 137.3, 134.5, 132.4, 130.9,128.6, 128.3, 127.4, 121.4, 112.9, 21.4; HRMS (EI) m/z: calcd forC₁₄H₁₂O₂: 212.0837. found: 212.0827; white solid, mp: 148-150° C.

General Procedure for the Synthesis of Triflates 5, 17, 30 and 37

To a suspension of biphenyl (1 equiv) and pyridine (3 equiv) in dryCH₂Cl₂ (30 mL), triflic anhydride (1.5 equiv) solved in dry CH₂Cl₂ (20mL) was added dropping under nitrogen atmosphere. The mixture wasstirred overnight at r.t. and quenched with NaHCO₃ satured solution (10mL). The aqueous layer was extracted with CH₂Cl₂ and the combinedorganic layers were dried over Na₂SO₄, filtered, concentrated in vacuoand purified by flash chromatography on silica gel.

Example 3 2-formyl-3′-methylbiphenyl-4-yl trifluoromethanesulfonate (5a)

Yield 86% (hexane/AcOEt 10:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 9.84 (s,1H), 7.81 (d, J=1.8 Hz, 1H), 7.46 (d, J=3.0 Hz, 2H), 7.31 (t, J=7.5 Hz,1H), 7.22 (d, J=7.5 Hz, 1H), 7.08 (d, J=8.7 Hz, 2H), 2.35 (s, 3H); ¹⁹FNMR (282 MHz, CDCl₃) δ ppm: −73.19 (s, 3F); ¹³C NMR (75 MHz, CDCl₃) δppm: 190.4, 148.9, 146.0, 138.6, 135.7, 135.2, 133.0, 130.7, 129.6,128.6, 127.1, 126.1, 120.0, 118.7 (q, ¹J=320.6 Hz), 21.4; HRMS (EI) m/z:calcd for C₁₅H₁₁F₃O₄S: 344.0330. found: 344.0325; white solid, mp:60-62° C.

Example 4 (E)-3-(2-bromo-5-hydroxyphenyl)acrylic acid (8)

A mixture of bromoaryl 3 (5.5 g, 27.0 mmol), malonic acid (2.85 g, 27.0mmol), pyridine (15 mL) and piperidine (0.5 mL) as catalyst were stirredovernight at 100° C. Thereafter, water (5 mL) was added and the mixturewas neutralized with concentrated HCl. The resulting precipitate wasfiltered and crystallized from methanol to give 4.72 g of 7 as a whitesolid. Yield 71%. ¹H NMR (300 MHz, CD₃COCD₃) δ ppm: 7.95 (d, J=15.8 Hz,1H), 7.49 (d, J=8.4 Hz, 1H), 7.29 (d, J=3.0 Hz, 1H), 6.88 (dd, J₁=8.4Hz, J₂=3.0 Hz, 1H), 6.44 (d, J=15.8 Hz, 1H), 2.88 (br s, 1H); ¹³C NMR(75 MHz, CD₃COCD₃) δ ppm: 168.2, 159.1, 144.4, 136.8, 135.9, 123.1,121.2, 116.2, 104.2; HRMS (EI) m/z: calcd for C₉H₇BrO₃: 241.9579. found:241.9515; mp: 208-210° C.

Example 5 (E)-ethyl 3-(2-bromo-5-hydroxyphenyl)acrylate (9)

A solution of acrylic acid 8 (4.35 g, 18.0 mmol) in dry ethanol (50 mL)with a small quantity of acid resine DOWEX™ (300 mg) was refluxed for 24h. The reaction mixture was filtered, the solvent was evaporated invacuo and the crude reaction product was purificated by means ofchromatography on silica gel (hexane/AcOEt 10:1) to give 4.36 g of ester9 as a white solid. Yield 90%. ¹H RMN (300 MHz, CD₃COCD₃) δ ppm: 8.82(br s, 1H), 7.94 (d, J=16.1 Hz, 1H), 7.49 (d, J=8.7 Hz, 1H), 7.28 (d,J=2.9 Hz, 1H), 6.88 (dd, J₁=8.7 Hz, J₂=2.9 Hz, 1H), 6.45 (d, J=16.1 Hz,1H), 4.24 (q, J=7.1 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H); ¹³C RMN (75 MHz,CD₃COCD₃) δ ppm: 167.5, 159.1, 144.0, 136.7, 135.9, 123.0, 121.3, 116.2,115.8, 62.1, 15.6; HRMS (EI) m/z: calcd for C₁₁H₁₁BrO₃: 269.9892. found:269.9886; mp: 96-98° C.

Example 6 (E)-ethyl 3-[5-(benzyloxy)-2-bromophenyl]acrylate (10)

To a solution of ester 9 (4.9 g, 18.0 mmol) in anhydrous DMF (20 mL) wasadded potassium carbonate (5 g, 36.0 mmol) and benzyl bromide (3.38 g,19.8 mmol). The reaction mixture was stirred overnight at roomtemperature, filtered and the solvent was removed under reducedpressure. The resulting crude reaction product was suspended in waterand extracted with AcOEt. The combined organic layers were dried overNa₂SO₄, filtered, and the volatiles were removed in vacuo to give 6.06 gof bromoaryl 10 as a white solid. Yield 93%. ¹H NMR (300 MHz, CDCl₃) δppm: 7.94 (d, J=15.9 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 7.38-7.25 (m, 5H),7.14 (d, J=3.0 Hz, 1H), 6.81 (dd, J₁=9.0 Hz, J₂=3.0 Hz, 1H), 6.29 (d,J=15.9 Hz, 1H), 5.00 (s, 2H), 4.23 (q, J=7.1 Hz, 2H), 1.29 (t, J=7.1 Hz,3H); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 166.2, 158.0, 142.8, 136.1, 135.1,133.9, 128.6, 128.2, 127.4, 121.1, 118.3, 116.1, 113.6, 70.2, 60.6,14.2; HRMS (EI) m/z: calcd for C₁₈H₁₇BrO₃: 360.0361. found: 360.0361;mp: 72-74° C.

General Procedure for the Synthesis of Boronates 6, 27 and 35

Haloaryl (1 equiv), bis(pinacolato)diboron (1.1 equiv), potassiumacetate (3 equiv), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (0.03 equiv) were dissolved in anhydrousdimethylsulfoxide (15 mL) and the resulting mixture was heated overnightat 110° C. under inert atmosphere. Then, solvent was removed underreduced pressure and the residue was suspended in water and extractedwith AcOEt. The organic layers were dried over Na₂SO₄, filtered, andevaporated. The crude reaction product was purified by means of flashchromatography on silica gel.

Example 7 (E)-ethyl3-[5-(benzyloxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acrylate(6)

Yield 60% (hexane/AcOEt 20:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 8.54 (d,J=16.2 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.40-7.24 (m, 5H), 7.21 (d,J=2.4 Hz, 1H), 6.92 (dd, J₁=8.4 Hz, J₂=2.4 Hz, 1H), 6.28 (d, J=16.2 Hz,1H), 5.05 (s, 2H), 4.20 (q, J=7.1 Hz, 2H), 1.30 (s, 12H), 1.29 (t, J=7.1Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 167.1, 161.0, 145.5, 142.3,138.1, 136.5, 128.6, 128.1, 127.4, 119.2, 115.8, 111.6, 83.8, 69.8,60.3, 24.8, 14.3; HRMS (EI) m/z: calcd for C₂₄H₂₉BO₅: 407.2144. found:407.2103; white solid, mp: 108-110° C.

General Procedure for the Synthesis of Terphenyls 7, 18, 21j, 28, 31 and38

Triflate (1 equiv), boronate (1.2 equiv) and palladiumtetrakistriphenylphosfine (0.03 equiv) were dissolved in DME/EtOH (9:1).Then, a 2 M aq. Na₂CO₃ solution (2 equiv) was added to this yellowsolution and the resulting mixture was refluxed overnight. Afterconcentrating the mixture in vacuo the residue was taken up in water andextracted with AcOEt. The combined organic fractions were dried overNa₂SO₄, filtered, and evaporated. The crude reaction product waspurified by means of flash chromatography on silica gel.

Example 8 ethyl(E)-3-[4″-(benzyloxy)-2′-formyl-3-methyl-(1,1′;4′,1″)terphenyl-2″-yl]acrylate(7a)

Yield 85% (hexane/AcOEt 10:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 10.07 (s,1H), 8.06-7.97 (m, 1H), 7.74 (d, J=15.9 Hz, 1H), 7.63-7.23 (m, 13H),7.13 (dd, J₁=8.6 Hz, J₂=2.3 Hz, 1H), 6.45 (d, J=15.9 Hz, 1H), 5.18 (s,2H), 4.25 (q, J=7.1 Hz, 2H), 2.48 (s, 3H), 1.33 (t, J=7.2 Hz, 3H); ¹³CNMR (75 MHz, CDCl₃) δ ppm: 192.3, 166.6, 158.5, 144.9, 143.0, 139.1,138.2, 137.2, 136.5, 134.9, 134.3, 133.7, 133.6, 131.7, 130.8, 130.6,128.9, 128.6, 128.4, 128.3, 128.1, 127.5, 127.3, 119.9, 116.9, 112.5,70.2, 60.4, 21.4, 14.2; HRMS (EI) m/z: calcd for C₃₂H₂₈O₄: 476.1988.found: 476.1985; white solid, mp: 90-92° C.

General Procedure for the Terphenyl Hydrogenation (Compounds 11, 13, 19and 39)

A solution of terphenyl in AcOEt (15 mL) was hydrogenated overnight atroom temperature under the following conditions:

1) 10% palladium hydroxide on carbon as catalyst (25% w/w) and 25 atm ofpressure or

2) 10% palladium on carbon as catalyst (25% w/w) and 1 atm of pressure.Thereafter, the mixture was filtered over Celite and the filtratesconcentrated in vacuo. The crude reaction product was purified by meansof chromatography on silica gel.

Example 9 ethyl3-[4″-hydroxy-2′-(hydroxymethyl)-3-methyl-(1,1%4′,1″)terphenyl-2″-yl]propionate(13a)

Yield 80% (hexane/AcOEt 5:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.39 (s,1H), 7.27-7.07 (m, 6H), 6.99 (dd, J₁=8.1 Hz, J₂=2.1 Hz, 1H), 6.68 (s,1H), 6.64 (dd, J₁=8.1 Hz, J₂=2.4 Hz, 1H), 4.59 (s, 2H), 3.97 (q, J=7.0Hz, 2H), 2.81 (t, J=7.8 Hz, 2H), 2.36 (t, J=7.8 Hz, 2H), 2.32 (s, 3H),1.09 (t, J=7.1 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 173.6, 155.6,140.5, 140.3, 139.6, 139.3, 137.9, 137.7, 133.6, 131.5, 129.9, 129.2,128.5, 128.1, 128.0, 126.2, 115.9, 113.6, 63.1, 60.7, 35.4, 28.4, 21.5,14.1; HRMS (EI) m/z: calcd for C₂₅H₂₆O₄: 390.1831. found: 390.1833;white solid, mp: 57-59° C.

General Procedure for the Basic Hydrolysis of Esters (Compounds 1, 2a,12, 15, 20, 22 and 24)

Ester (1 equiv) was dissolved in a 4:1 tetrahydrofuran/water mixture (5mL), monohydrated lithium hydroxide (3 equiv) added and the reaction wasstirred at room temperature until completion. THF was removed underreduced pressure, the aqueous layer was acidified with 1 M HCl solution,and extracted with AcOEt. The organic layers were combined, dried overNa₂SO₄, filtered and removed in vacuo under reduced pressure.

Example 103-[4″-hydroxy-2′-(hydroxymethyl)-3-methyl-(1,1%4′,1″)terphenyl-2″-yl]propionicacid (1a)

Yield 99%. ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.50-7.12 (m, 7H), 7.03 (d,J=8.1 Hz, 1H), 6.82-6.62 (m, 2H), 6.08 (br s, 1H), 4.64 (s, 2H), 2.85(t, J=6.3 Hz, 2H), 2.42 (t, J=6.9 Hz, 2H), 2.37 (s, 3H); ¹³C NMR (75MHz, CDCl₃) δ ppm: 177.8, 155.2, 140.4, 140.2, 139.7, 139.0, 137.9,137.2, 133.8, 131.5, 129.9 (2×), 129.3, 128.5, 128.1, 128.0, 126.2,115.7, 113.6, 62.9, 35.0, 29.7, 21.4; HRMS (EI) m/z: calcd for C₂₃H₂₂O₄:362.1518. found: 362.1516.

General Procedure for the Fluorination of Hydroxyls and Aldehydes(Compounds 14, 16, 21k and 21l)

Biphenyl or terphenyl (1 equiv) were dissolved in anhydrousdichloromethane (10 mL), DAST (2 equiv) was added and the reaction wasstirred overnight at room temperature under nitrogen atmosphere. Then,the reaction mixture was hydrolyzed by addition of saturated NaHCO₃solution. The aqueous layer was extracted with dichloromethane, thecombined organic layers were dried over Na₂SO₄, filtered, and thesolvent removed in vacuo under reduced pressure. The resulting crudereaction product was purified by means of flash chromatography on silicagel.

Example 11 ethyl3-[2′-(fluoromethyl)-4″-hydroxy-3-methyl-(1,1%4′,1″)terphenyl-2″-yl]propionate(14a)

Yield 40% (hexane/AcOEt 10:1). ¹H RMN (300 MHz, CDCl₃) δ ppm: 7.39 (s,1H), 7.31-7.10 (m, 6H), 7.05 (d, J=8.4 Hz, 1H), 6.73 (d, J=2.4 Hz, 1H),6.69 (dd, J₁=8.3 Hz, J₂=2.3 Hz, 1H), 5.71 (br s, 1H), 5.25 (d, J=48.0Hz, 2H), 4.01 (q, J=7.1 Hz, 2H), 2.87 (t, J=7.8 Hz, 2H), 2.41 (t, J=7.8Hz, 2H), 2.34 (s, 3H), 1.12 (t, J=7.1 Hz, 3H); ¹⁹F RMN (282 MHz, CDCl₃)δ ppm: −200.6 (t, J=47.9 Hz, 1F); ¹³C RMN (75 MHz, CDCl₃) δ ppm: 173.3,155.3, 140.6, 140.5, 139.7, 139.4, 137.9, 133.6, 133.1 (d, ²J=15.8 Hz),131.6, 130.5 (d, ³J=6.5 Hz), 130.0 (2×), 129.9, 128.2, 128.1, 126.4,115.7, 113.4, 82.8 (d, ¹J=163.9 Hz), 60.6, 35.3, 28.3, 21.5, 14.1; HRMS(EI) m/z: calcd for C₂₅H₂₅FO₃: 392.1788. found: 392.1786.

General Procedure for the Alkylation Reaction (Compounds 21a-h and 23)

A solution of terphenyl (1 equiv), potassium carbonate (2 equiv) andalkyl halide (3 equiv) in acetone (5 mL) was heated at 70° C. in amicrowave flask until completion. Then, the solvent was removed in vacuoand the crude reaction product was suspended in water. The aqueous layerwas extracted with AcOEt and filtered and the combined organic layerswere dried over Na₂SO₄, filtered and removed in vacuo under reducedpressure. The resulting crude reaction product was purified by means offlash chromatography on silica gel.

Example 12 ethyl3-[2′-(hydroxymethyl)-4″-metoxy-3-methyl-(1,1%4′,1″)terphenyl-2″-yl]propionate(21a)

Yield 80% (hexane/AcOEt 10:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.42 (d,J=1.5 Hz, 1H), 7.30-7.22 (m, 2H), 7.21-7.10 (m, 5H), 6.79 (d, J=2.8 Hz,1H), 6.76 (dd, J₁=8.3 Hz, J₂=2.8 Hz, 1H), 4.60 (d, J=5.0 Hz, 2H), 4.02(q, J=7.1 Hz, 2H), 3.78 (s, 3H), 2.90 (t, J=8.0 Hz, 2H), 2.45 (t, J=8.0Hz, 2H), 2.35 (s, 3H), 1.14 (t, J=7.1 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δppm: 173.1, 159.0, 140.4, 140.3, 139.7, 139.4, 137.9, 134.0, 131.3,130.0, 129.9, 129.2, 128.5, 128.2, 128.0, 126.2, 114.6, 111.6, 63.3,60.5, 55.3, 35.6, 28.7, 21.5, 14.2; HRMS (EI) m/z: calcd for C₂₆H₂₈O₄:404.1987. found: 404.1992.

Example 133-[4″-hydroxy-2′-(hydroxymethyl)-3-(trifluoromethyl)-(1,1%4′,1″)terphenyl-2″-yl]propionicacid (1b)

Yield 98%. ¹H NMR (300 MHz, CD₃COCD₃) δ ppm: 8.40 (br s, 1H), 7.86 (s,1H), 7.80 (d, J=6.9 Hz, 1H), 7.77-7.66 (m, 2H), 7.60 (s, 1H), 7.37 (d,J=8.1 Hz, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.89 (d,J=2.1 Hz, 1H), 6.79 (dd, J₁=8.3 Hz, J₂=2.6 Hz, 1H), 4.59 (s, 2H), 2.92(t, J=7.8 Hz, 2H), 2.50 (t, J=7.7 Hz, 2H); ¹⁹F NMR (282 MHz, CD₃COCD₃) δppm: −61.89 (s, 3F); ¹³C NMR (75 MHz, CD₃COCD₃) δ ppm: 175.0, 158.8,143.6, 143.5, 141.5, 140.9, 139.5, 135.0, 134.7, 133.0, 131.8, 131.6 (q,²J=31.7 Hz), 131.4, 130.9, 130.2, 127.7 (q, ³J=3.8 Hz), 126.4 (q,¹J=270.1 Hz), 125.6 (q, ³J=3.8 Hz), 117.6, 115.1, 63.6, 36.4, 30.0; HRMS(EI) m/z: calcd for C₂₃H₁₉F₃O₄: 416.1235. found: 416.1226; white solid,mp: 124-126° C.

Example 143-[4-hydroxy-3′-(hydroxymethyl)-4′-(pyridin-3-yl)biphenyl-2-yl]propionicacid (1c)

Yield 76%. ¹H NMR (300 MHz, MeOD+drops CDCl₃) δ ppm: 8.63 (d, J=1.5 Hz,1H), 8.54 (dd, J₁=4.8 Hz, J₂=1.2 Hz, 1H), 7.95 (ddd, J₁=7.9 Hz, J₂=2.2Hz, J₃=1.7 Hz, 1H), 7.55-7.47 (m, 2H), 7.31 (d, J=1.1 Hz, 1H), 7.05 (d,J=8.3 Hz, 1H), 6.79 (d, J=2.5 Hz, 1H), 6.71 (dd, J₁=8.3 Hz, J₂=2.6 Hz,1H), 4.53 (s, 2H), 2.90 (t, J=8.0 Hz, 2H), 2.44 (t, J=8.0 Hz, 2H); ¹³CNMR (75 MHz, MeOD+drops CDCl₃) δ ppm: 174.7, 155.9, 148.0, 146.4, 141.3,138.5, 137.5, 136.9, 136.3, 134.6, 131.8, 130.1, 129.3, 128.8, 127.8,122.7, 114.5, 112.2, 60.8, 34.2, 27.4; HRMS (EI) m/z: calcd forC₂₁H₁₉NO₄: 350.1392 (M+1). found: 350.1393; white solid, mp: 197-199° C.

Example 153-[4″-hydroxy-2″-isopropyl-3-methyl-(1,1′;4′,1″)terphenyl-2′-yl]propionicacid (2a)

Yield 97%. ¹H NMR (300 MHz, CDCl₃+drops MeOD) δ ppm: 7.18-7.26 (m, 1H),7.02-7.15 (m, 6H), 6.97 (d, J=8.1 Hz, 1H), 6.78 (d, J=2.7 Hz, 1H), 6.61(dd, J₁=8.1 Hz, J₂=2.7 Hz, 1H), 3.00 (sep, J=6.9 Hz, 1H), 2.89 (t, J=8.1Hz, 2H), 2.38 (t, J=8.1 Hz, 2H), 2.32 (s, 3H), 1.08 (d, J=6.9 Hz, 6H);¹³C NMR (75 MHz, CDCl₃+drops MeOD) δ ppm: 175.6, 156.0, 148.0, 141.3,141.1, 140.1, 137.7, 137.3, 132.7, 131.0, 130.1, 129.9, 129.7, 128.0,127.6, 127.3, 126.1, 112.4, 112.2, 35.0, 29.4, 28.2, 24.1, 21.3; HRMS(EI) m/z: calcd for C₂₅H₂₆O₃: 374.1882. found: 374.1881; white solid,mp: 183-185° C.

Example 16 4-hydroxy-3′-(trifluoromethyl)biphenyl-2-carbaldehyde (4b)

Yield 82% (hexane/AcOEt 10:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 9.89 (s,1H), 7.69 (d, J=7.8 Hz, 1H), 7.63 (s, 1H), 7.59 (t, J=7.5 Hz, 1H), 7.52(t, J=3.0 Hz, 2H), 7.35 (d, J=8.3 Hz, 1H), 7.19 (dd, J₁=8.3 Hz, J₂=2.8Hz, 1H), 6.38 (br s, 1H); ¹⁹F NMR (282 MHz, CDCl₃) δ ppm: −63.11 (s,3F); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 192.1, 156.2, 138.3, 137.3, 134.5,133.6, 132.5131.0 (q, ²J=32.5 Hz), 128.9, 126.6 (q, ³J=3.7 Hz), 124.7(q, ³J=3.8 Hz), 122.9 (q, ¹J=270.9 Hz), 121.8, 113.6; HRMS (EI) m/z:calcd for C₁₄H₉F₃O₂: 266.0554. found: 266.0537; yellow solid, mp:100-102° C.

Example 17 5-hydroxy-2-(pyridin-3-yl)benzaldehyde (4c)

Yield 99% (CH₂Cl₂/AcOEt 4:1). ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 10.16 (s,1H), 9.80 (s, 1H), 8.61 (dd, J₁=4.8 Hz, J₂=1.5 Hz, 1H), 8.59 (d, J=2.1Hz, 1H), 7.83 (dt, J₁=7.8 Hz, J₂=2.0 Hz, 1H), 7.49 (dd, J₁=7.2 Hz,J₂=4.8 Hz, 1H), 7.38 (d, J=8.1 Hz, 1H), 7.33 (d, J=2.7 Hz, 1H), 7.18(dd, J₁=8.1 Hz, J₂=2.4 Hz, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ ppm: 191.2,157.5, 149.8, 148.3, 137.2, 134.3, 133.3, 132.6, 132.3, 123.2, 121.4,113.6; HRMS (EI) m/z: calcd for C₁₂H₉NO₂: 199.0633. found: 199.0607;white solid, mp: 182-184° C.

Example 18 2-formyl-3′-(trifluoromethyl)biphenyl-4-yltrifluoromethanesulfonate (5b)

Yield 90% (hexane/AcOEt 10:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 9.90 (s,1H), 7.94 (d, J=1.7 Hz, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.68 (d, J=7.2 Hz,2H), 7.61-7.53 (m, 3H); ¹⁹F NMR (282 MHz, CDCl₃) δ ppm: −63.19 (s, 3F),−73.15 (s, 3F); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 189.3, 149.5, 144.0,136.8, 135.3, 133.3, 133.1, 131.5 (q, ²J=32.6 Hz), 129.3, 126.5, 126.4(q, ³J=3.6 Hz), 125.7 (q, ³J=3.6 Hz), 123.7 (q, ¹J=270.8 Hz), 120.6,118.7 (q, ¹J=318.9 Hz); HRMS (EI) m/z: calcd for C₁₅H₈F₆O₄S: 398.0047.found: 398.0039.

Example 19 3-formyl-4-(pyridin-3-yl)phenyl trifluoromethanesulfonate(5c)

Yield 60% (CH₂Cl₂/AcOEt 5:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 9.93 (s,1H), 8.75 (dt, J₁=4.8 Hz, J₂=0.9 Hz, 1H), 8.67 (d, J=2.4 Hz, 1H), 7.95(d, J=2.4 Hz, 1H), 7.73 (dt, J₁=7.8 Hz, J₂=2.7 Hz, 1H), 7.61 (dd, J₁=8.1Hz, J₂=2.4 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.47 (dd, J₁=7.8 Hz, J₂=4.8Hz, 1H); ¹⁹F NMR (282 MHz, CDCl₃) δ ppm: −73.13 (s, 3F); ¹³C NMR (75MHz, CDCl₃) δ ppm: 189.0, 150.1, 150.0, 149.6, 141.7, 137.1, 135.4,133.2, 131.8, 126.6, 123.4, 120.8, 118.7 (q, ¹J=318.9 Hz); HRMS (EI)m/z: calcd for C₁₃H₈F₃NO₄S: 332.0204 (M+1). found: 332.0124.

Example 20 (E)-ethyl3-[4″-(benzyloxy)-2′-formyl-3-(trifluoromethyl)-(1,1′;4′,1″)terphenyl-2″-yl]acrylate(7b)

Yield 86% (hexane/AcOEt 10:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 10.00 (s,1H), 7.99 (d, J=2.1 Hz, 1H), 7.74 (br s, 2H), 7.67 (d, J=16.2 Hz, 2H),7.63 (d, J=3.0 Hz, 1H), 7.58 (dd, J₁=7.8 Hz, J₂=1.8 Hz, 1H), 7.51-7.41(m, 5H), 7.39 (dd, J₁=5.7 Hz, J₂=1.8 Hz, 1H), 7.35 (d, J=8.7 Hz, 2H),7.32 (d, J=2.7 Hz, 1H), 7.11 (dd, J₁=8.4 Hz, J₂=2.7 Hz, 1H), 6.41 (d,J=15.9 Hz, 1H), 5.16 (s, 2H), 4.22 (q, J=7.0 Hz, 2H), 1.29 (t, J=7.2 Hz,3H); ¹⁹F NMR (282 MHz, CDCl₃) δ ppm: −63.16 (s, 3F); ¹³C NMR (75 MHz,CDCl₃) δ ppm: 191.3, 166.6, 158.7, 142.9, 142.8, 140.2, 138.4, 136.5,135.2, 133.9, 133.8, 133.6, 133.4, 131.7, 131.1 (q, ²J=32.4 Hz), 130.8,129.2, 129.0, 128.7, 128.2, 127.5, 126.5 (q, ³J=3.7 Hz), 125.0 (q,³J=3.9 Hz), 123.9 (q, ¹J=270.4 Hz), 120.2, 117.0, 112.7, 70.3, 60.5,14.2; HRMS (EI) m/z: calcd for C₃₂H₂₅F₃O₄: 530.1705. found: 530.1681;white solid, mp: 116-118° C.

Example 21 (E)-ethyl3-[4-(benzyloxy)-3′-formyl-4′-(pyridin-3-yl)biphenyl-2-yl]acrylate (7c)

Yield 82% (CH₂Cl₂/AcOEt 10:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 10.02 (s,1H), 8.71 (dd, J₁=6.7 Hz, J₂=1.8 Hz, 1H), 7.99 (d, J=2.1 Hz, 1H), 7.77(ddd, J₁=7.8 Hz, J₂=2.2 Hz, J₃=1.7 Hz, 1H), 7.66 (d, J=15.9 Hz, 1H),7.58 (dd, J₁=7.9 Hz, J₂=2.0 Hz, 1H), 7.51-7.28 (m, 10H), 7.09 (dd,J₁=8.5 Hz, J₂=2.6 Hz, 1H), 6.41 (d, J=15.8 Hz, 1H), 5.14 (s, 2H), 4.20(q, J=7.1 Hz, 2H), 1.28 (t, J=7.1 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δppm: 190.9, 166.5, 158.6, 150.0, 149.3, 142.7, 140.4, 140.2, 137.1,136.4, 135.1, 133.7, 133.7, 133.3, 131.6, 130.9, 129.4, 128.6, 128.1,127.4, 123.1, 120.2, 116.9, 112.6, 70.1, 60.4, 14.2; HRMS (EI) m/z:calcd for C₃₀H₂₅NO₄: 464.1862 (M+1). found: 464.1869; yellowish solid,mp: 126-128° C.

Example 22 ethyl3-[4″-hydroxy-2′,3-dimethyl-(1,1%4′,1″)terphenyl-2″-yl]propionate (11a)

Yield 90% (hexane/AcOEt 5:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.25 (t,J=7.4 Hz, 1H), 7.20-7.01 (m, 7H), 6.72 (d, J=2.1 Hz, 1H), 6.67 (dd,J₁=8.4 Hz, J₂=2.4 Hz, 1H), 5.18 (s, 1H), 4.02 (q, J=7.1 Hz, 2H), 2.88(t, J=8.0 Hz, 2H), 2.41 (t, J=7.8 Hz, 2H), 2.34 (s, 3H), 2.23 (s, 3H),1.14 (t, J=7.2 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 173.2, 154.9,141.6, 140.4, 140.0, 139.5, 137.6, 135.1, 134.4, 131.5, 131.3, 130.0,129.6, 127.9, 127.5, 126.7, 126.3, 115.6, 113.2, 60.5, 35.4, 28.4, 21.5,20.6, 14.1; HRMS (EI) m/z: calcd for C₂₅H₂₆O₃: 374.1882. found:374.1881.

Example 23 ethyl3-[4″-hydroxy-2′-methyl-3-(trifluoromethyl)-(1,1%4′,1″)terphenyl-2″-yl]propionate(11b)

Yield 83% (hexane/AcOEt 10:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.60 (s,1H), 7.58-7.52 (m, 1H), 7.50 (d, J=6.0 Hz, 2H), 7.19 (d, J=7.5 Hz, 1H),7.14 (br s, 1H), 7.12 (dd, J₁=7.5 Hz, J₂=1.5 Hz, 1H), 7.06 (d, J=8.4 Hz,1H), 6.75 (d, J=2.7 Hz, 1H), 6.70 (dd, J₁=8.4 Hz, J₂=2.7 Hz, 1H), 5.31(s, 1H), 4.04 (q, J=7.2 Hz, 2H), 2.90 (t, J=8.0 Hz, 2H), 2.43 (t, J=8.0Hz, 2H), 2.24 (s, 3H), 1.16 (t, J=7.2 Hz, 3H); ¹⁹F NMR (282 MHz, CDCl₃)δ ppm: −63.05 (s, 3F); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 173.2, 155.1,142.4, 140.9, 139.5, 138.8, 135.1, 134.1, 132.6, 131.6, 131.5, 130.6 (q,²J=31.9 Hz), 129.5, 128.6, 127.0, 126.0 (q, ³J=3.8 Hz), 124.2 (q,¹J=270.5 Hz), 123.6 (q, ³J=4.0 Hz), 115.7, 113.3, 60.5, 35.4, 28.4,20.4, 14.1; HRMS (EI) m/z: calcd for C₂₅H₂₃F₃O₃: 428.1599. found:428.1606.

Example 243-[4″-hydroxy-2′,3-dimethyl-(1,1′;4′,1″)terphenyl-2″-yl]propionic acid(12a)

Yield 99%. ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.25 (t, J=7.4 Hz, 1H),7.21-7.03 (m, 7H), 6.79-6.63 (m, 2H), 2.89 (t, J=7.7 Hz, 2H), 2.45 (t,J=7.7 Hz, 2H), 2.35 (s, 3H), 2.24 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δppm: 178.4, 154.9, 141.6, 140.5, 139.9, 139.1, 137.6, 135.1, 134.5,131.6, 131.2, 130.0, 129.6, 127.9, 127.5, 126.7, 126.3, 115.6, 113.4,34.9, 28.1, 21.5, 20.6; HRMS (EI) m/z: calcd for C₂₃H₂₂O₃: 346.1569.found: 346.1562.

Example 253-[4″-hydroxy-2′-methyl-3-(trifluoromethyl)-(1,1′;4′,1″)terphenyl-2″-yl]propionicacid (12b)

Yield 99%. ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.57 (d, J=11.4 Hz, 2H), 7.49(d, J=6.6 Hz, 2H), 7.18 (d, J=7.5 Hz, 1H), 7.13 (br s, 1H), 7.10 (dd,J₁=8.1 Hz, J₂=1.5 Hz, 1H), 7.06 (d, J=7.8 Hz, 1H), 6.74 (d, J=2.7 Hz,1H), 6.70 (dd, J₁=8.3 Hz, J₂=2.6 Hz, 1H), 2.89 (t, J=7.8 Hz, 2H), 2.46(t, J=8.0 Hz, 2H), 2.23 (s, 3H); ¹⁹F NMR (282 MHz, CDCl₃) δ ppm: −63.03(s, 3F); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 178.4, 155.0, 142.3, 140.7,139.1, 138.9, 135.1, 134.2, 132.6, 131.6, 131.5, 130.6 (q, ²J=32.0 Hz),129.6, 128.6, 127.0, 126.0 (q, ³J=3.8), 124.2 (q, ¹J=270.5 Hz), 123.6(q, ³J=3.9 Hz), 115.6, 113.4, 34.9, 28.0, 20.4; HRMS (EI) m/z: calcd forC₂₃H₁₉F₃O₃: 400.1286. found: 400.1282.

Example 26 ethyl3-[4″-hydroxy-2′-(hydroxymethyl)-3-(trifluoromethyl)-(1,1′;4′,1″)terphenyl-2″-yl]propionate(13b)

Yield 84% (hexane/AcOEt 4:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.71 (s,1H), 7.64 (d, J=7.5 Hz, 2H), 7.54 (t, J=8.1 Hz, 2H), 7.31 (d, J=8.1 Hz,2H), 7.09 (d, J=8.4 Hz, 1H), 6.77 (d, J=2.4 Hz, 1H), 6.73 (dd, J₁=8.3Hz, J₂=2.6 Hz, 1H), 6.39 (br s, 1H), 4.63 (s, 2H), 4.07 (q, J=7.2 Hz,2H), 2.91 (t, J=7.8 Hz, 2H), 2.68 (br s, 1H), 2.47 (t, J=7.8 Hz, 2H),1.19 (t, J=7.2 Hz, 3H); ¹⁹F NMR (282 MHz, CDCl₃) δ ppm: −63.01 (s, 3F);¹³C NMR (75 MHz, CDCl₃) δ ppm: 173.6, 155.5, 141.3, 141.1, 139.3, 138.2,137.7, 133.5, 132.6, 131.4, 130.7 (q, ²J=32.0 Hz), 129.9, 129.7, 128.8,128.7, 126.0 (q, ³J=4.1 Hz), 124.1 (q, ¹J=270.8 Hz), 124.0 (q, ³J=3.8Hz), 115.8, 113.5, 62.9, 60.7, 35.4, 28.4, 14.1; HRMS (EI) m/z: calcdfor C₂₅H₂₃F₃O₄: 444.1548. found: 444.1535.

Example 27 ethyl3-[4-hydroxy-3′-(hydroxymethyl)-4′-(pyridin-3-yl)biphenyl-2-yl]propionate(13c)

Yield 74% (CH₂Cl₂/AcOEt 1:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 8.56 (d,J=1.5 Hz, 1H), 8.45 (dd, J₁=4.9 Hz, J₂=1.5 Hz, 1H), 7.80 (td, J₁=7.9 Hz,J₂=1.7 Hz, J₃=1.7 Hz, 1H), 7.46 (s, 1H), 7.31 (dd, J₁=7.8 Hz, J₂=5.1 Hz,1H), 7.23-7.14 (m, 2H), 6.93 (d, J=8.4 Hz, 1H), 6.74 (d, J=2.1 Hz, 1H),6.67 (dd, J₁=8.4 Hz, J₂=2.4 Hz, 1H), 4.54 (s, 2H), 3.93 (q, J=7.2 Hz,2H), 2.81 (t, J=7.8 Hz, 2H), 2.36 (t, J=7.8 Hz, 2H), 1.06 (t, J=7.2 Hz,3H); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 173.3, 156.5, 148.8, 147.3, 141.8,139.0, 138.1, 137.6, 136.7, 135.2, 132.6, 131.3, 130.1, 129.8, 128.8,123.5, 115.9, 113.6, 62.4, 60.5, 35.3, 28.3, 14.0; HRMS (EI) m/z: calcdfor C₂₃H₂₃NO₄: 378.1705 (M+1). found: 378.1700; white solid, mp: 46-48°C.

Example 28 ethyl3-[2′-(fluoromethyl)-4″-hydroxy-3-(trifluoromethyl)-(1,1′;4′,1″)terphenyl-2″-yl]propionate(14b)

Yield 35% (hexane/AcOEt 10:1). ¹H RMN (300 MHz, CDCl₃) δ ppm: 7.73-7.48(m, 5H), 7.41-7.37 (m, 2H), 7.13 (d, J=8.2 Hz, 1H), 6.84 (d, J=2.4 Hz,1H), 6.79 (dd, J₁=8.2 Hz, J₂=2.6 Hz, 1H), 5.29 (d, J=48.0 Hz, 2H), 4.11(q, J=7.1 Hz, 2H), 2.96 (t, J=7.8 Hz, 2H), 2.51 (t, J=7.8 Hz, 2H), 1.21(t, J=7.1 Hz, 3H); ¹⁹F RMN (282 MHz, CDCl₃) δ ppm: −63.04 (s, 3F),−199.0 (t, J=48.2 Hz, 1F); ¹³C RMN (75 MHz, CDCl₃) δ ppm: 173.4, 155.6,141.5, 140.5, 139.3, 139.2, 133.2, 133.1 (d, ²J=15.6 Hz), 132.7, 131.5,131.2 (d, ³J=6.3 Hz), 130.8 (q, ²J=32.4 Hz), 130.3, 130.0, 128.8, 126.0(q, ³J=3.4 Hz), 124.3 (q, ³J=3.4 Hz), 124.0 (q, ¹J=272.5 Hz), 115.8,113.5, 82.6 (d, ¹J=165.6 Hz), 60.7, 35.3, 28.3, 14.1.

Example 29 ethyl3-[3′-(fluoromethyl)-4-hydroxy-4′-(pyridin-3-yl)biphenyl-2-yl]propionate(14c)

Yield 35% (CH₂Cl₂/AcOEt 5:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 8.72 (d,J=1.6 Hz, 1H), 8.68 (dd, J₁=4.9 Hz, J₂=1.6 Hz, 1H), 7.87 (ddd, J₁=7.8Hz, J₂=2.1 Hz, J₃=1.8 Hz, 1H), 7.51 (t, J=1.6 Hz, 1H), 7.50-7.36 (m,3H), 7.11 (d, J=8.2 Hz, 1H), 6.86 (d, J=2.4 Hz, 1H), 6.81 (dd, J₁=8.2Hz, J₂=2.6 Hz, 1H), 5.29 (d, J=48.0 Hz, 2H), 4.07 (q, J=7.1 Hz, 2H),2.94 (t, J=8.0 Hz, 2H), 2.48 (t, J=8.0 Hz, 2H), 1.19 (t, J=7.1 Hz, 3H);¹⁹F RMN (282 MHz, CDCl₃) δ ppm: −197.7 (t, J=48.0 Hz, 1F); ¹³C NMR (75MHz, CDCl₃) δ ppm: 172.9, 156.4, 149.2, 148.1, 142.0, 139.4, 137.4,136.6, 136.0, 133.3 (d, ²J=15.9 Hz), 132.5, 131.6 (d, ³J=6.1 Hz), 131.4,130.5, 130.2, 123.5, 116.0, 113.6, 82.6 (d, ¹J=166.1 Hz), 60.5, 35.3,28.3, 14.1.

Example 303-[2′-(fluoromethyl)-4″-hydroxy-3-methyl-(1,1′;4′,1″)terphenyl-2″-yl]propionicacid (15a)

Yield 99%. ¹H RMN (300 MHz, CDCl₃) δ ppm: 7.37 (s, 1H), 7.31-7.09 (m,6H), 7.05 (d, J=8.4 Hz, 1H), 6.73 (d, J=2.4 Hz, 1H), 6.68 (dd, J₁=8.3Hz, J₂=2.3 Hz, 1H), 5.24 (d, J=47.7 Hz, 2H), 2.86 (t, J=7.7 Hz, 2H),2.44 (t, J=7.7 Hz, 2H), 2.34 (s, 3H); ¹⁹F RMN (282 MHz, CDCl₃) δ ppm:−200.7 (t, J=47.9 Hz, 1F); ¹³C RMN (75 MHz, CDCl₃) δ ppm: 178.5, 155.1,140.7, 140.4, 139.6, 139.1, 137.9, 133.8, 133.2 (d, ²J=15.3 Hz), 131.7,130.5 (d, ³J=6.6 Hz), 130.0 (2×), 129.8, 128.2 (2×), 126.4, 115.7,113.5, 82.8 (d, ¹J=163.9 Hz), 34.9, 28.0, 21.5; HRMS (EI) m/z: calcd forC₂₃H₂₁FO₃: 364.1475. found: 364.1471.

Example 313-[2′-(fluoromethyl)-4″-hydroxy-3-(trifluoromethyl)-(1,1′;4′,1″)terphenyl-2″-yl]propionicacid (15b)

Yield 99%. ¹H RMN (300 MHz, CDCl₃) δ ppm: 7.72-7.53 (m, 5H), 7.48 (d,J=0.9 Hz, 1H), 7.36 (d, J=0.9 Hz, 2H), 7.12 (d, J=8.2 Hz, 1H), 6.84 (d,J=2.3 Hz, 1H), 6.78 (dd, J₁=8.2 Hz, J₂=2.4 Hz, 1H), 5.28 (d, J=47.9 Hz,2H), 2.94 (t, J=7.6 Hz, 2H), 2.53 (t, J=7.6 Hz, 2H); ¹⁹F RMN (282 MHz,CDCl₃) δ ppm: −63.04 (s, 3F), −199.0 (t, J=47.9 Hz, 1F); ¹³C RMN (75MHz, CDCl₃) δ ppm: 178.7, 155.4, 141.3, 140.5, 139.3, 139.0, 133.3,133.1 (d, ²J=15.9 Hz), 132.7, 131.6, 131.1 (d, ³J=6.1 Hz), 130.8 (q,²J=32.4 Hz), 130.2, 130.0, 128.8, 126.0 (q, ³J=3.1 Hz), 124.3 (q, ³J=3.1Hz), 124.0 (q, ¹J=272.5 Hz), 115.7, 113.6, 82.6 (d, ¹J=165.6 Hz), 34.9,27.9.

Example 323-[3′-(fluoromethyl)-4-hydroxy-4′-(pyridin-3-yl)biphenyl-2-yl]propionicacid (15c)

Yield 99%. ¹H NMR (300 MHz, CDCl₃+drops MeOD) δ ppm: 8.55 (s, 1H), 8.51(d, J=3.4 Hz, 1H), 7.87 (dt, J₁=7.8 Hz, J₂=1.8 Hz, 1H), 7.41 (t, J=1.5Hz, 1H), 7.40-7.27 (m, 3H), 7.00 (d, J=8.2 Hz, 1H), 6.73 (d, J=2.4 Hz,1H), 6.68 (dd, J₁=8.2 Hz, J₂=2.5 Hz, 1H), 5.18 (d, J=48.1 Hz, 2H), 2.83(t, J=8.0 Hz, 2H), 2.39 (t, J=8.0 Hz, 2H); ¹⁹F RMN (282 MHz, CDCl₃+dropsMeOD) δ ppm: −197.4 (t, J=48.1 Hz, 1F); ¹³C NMR (75 MHz, CDCl₃+dropsMeOD) δ ppm: 175.4, 156.4, 148.8, 147.7, 142.0, 139.1, 137.4, 136.3,136.0, 133.1 (d, ²J=15.7 Hz), 132.0, 131.4 (d, ³J=5.9 Hz), 131.1, 130.4,129.9, 123.4, 115.5, 113.3, 82.4 (d, ¹J=165.5 Hz), 35.0, 28.1; whitesolid, mp: 200-202° C.

Example 33 2-(difluoromethyl)-3′-methylbiphenyl-4-ol (16a)

Yield 79% (hexane/AcOEt 10:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.23 (t,J=7.5 Hz, 1H), 7.13 (t, J=8.1 Hz, 3H), 7.03 (d, J=8.4 Hz, 2H), 6.91 (dt,J₁=8.1 Hz, J₂=1.4 Hz, 1H), 6.42 (t, J=54.9 Hz, 1H), 2.33 (s, 3H); ¹⁹FNMR (282 MHz, CDCl₃) δ ppm: −108.38 (d, J=54.7 Hz, 2F); ¹³C NMR (75 MHz,CDCl₃) δ ppm: 155.1, 138.3, 138.1, 134.3 (t, ³J=6.7 Hz), 133.0 (t,²J=21.8 Hz), 131.7, 130.3, 128.3, 128.2, 126.6, 117.6 (t, ⁴J=1.9 Hz),112.9 (t, ¹J=234.9 Hz), 111.0 (t, ³J=5.3 Hz), 21.4; HRMS (EI) m/z: calcdfor C₁₄H₁₂F₂O: 234.0856. found: 234.0844; yellowish oil.

Example 34 2-(difluoromethyl)-3′-(trifluoromethyl)biphenyl-4-ol (16b)

Yield 56% (hexane/AcOEt 10:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.59 (d,J=7.7 Hz, 1H), 7.53 (br s, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.45 (d, J=7.7Hz, 1H), 7.19 (d, J=4.7 Hz, 1H), 7.16 (d, J=5.1 Hz, 1H), 6.96 (dt,J₁=8.4 Hz, J₂=1.3 Hz, 1H), 6.36 (t, J=54.8 Hz, 1H), 5.23 (s, 1H); ¹⁹FNMR (282 MHz, CDCl₃) δ ppm: −63.19 (s, 3F), −108.56 (d, J=54.8 Hz, 2F);¹³C NMR (75 MHz, CDCl₃) δ ppm: 155.7, 139.2, 133.2 (t, ²J=21.9 Hz),132.9, 132.4 (t, ³J=6.4 Hz), 131.9, 131.0 (q, ²J=32.2 Hz), 128.9, 126.2(q, ³J=3.8 Hz), 124.5 (q, ³J=3.7 Hz), 124.0 (q, ¹J=270.7 Hz), 118.0,112.6 (t, ¹J=235.7 Hz), 112.4 (t, ³J=5.7 Hz); HRMS (EI) m/z: calcd forC₁₄H₉F₅O: 288.0574. found: 288.0548; yellowish oil.

Example 35 2-(difluoromethyl)-3′-methylbiphenyl-4-yltrifluoromethanesulfonate (17a)

Yield 79% (hexane/AcOEt 10:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.59 (brs, 1H), 7.36 (br s, 2H), 7.28 (t, J=7.5 Hz, 1H), 7.19 (d, J=7.5 Hz, 1H),7.05 (d, J=8.4 Hz, 2H), 6.43 (t, J=51.2 Hz, 1H), 2.34 (s, 3H); ¹⁹F NMR(282 MHz, CDCl₃) δ ppm: −73.22 (s, 3F), −108.83 (d, J=51.2 Hz, 2F); ¹³CNMR (75 MHz, CDCl₃) δ ppm: 155.1, 138.3, 138.1, 134.3 (t, ³J=6.6 Hz),133.0 (t, ²J=21.8 Hz), 131.7, 130.3, 128.3, 128.2, 126.7, 118.7 (q,¹J=318.9 Hz), 117.8 (t, ⁴J=1.9 Hz), 112.9 (t, ¹J=234.9 Hz), 112.0 (t,³J=5.3 Hz), 21.4; HRMS (EI) m/z: calcd for C₁₅H₁₁F₅O₃S: 366.0349. found:366.0315.

Example 36 2-(difluoromethyl)-3′-(trifluoromethyl)biphenyl-4-yltrifluoromethanesulfonate (17b)

Yield 83% (hexane/AcOEt 10:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.66 (d,J=7.8 Hz, 1H), 7.62 (br s, 1H), 7.55 (t, J=7.8 Hz, 2H), 7.47 (d, J=7.5Hz, 1H), 7.39 (t, J=9.3 Hz, 2H), 6.36 (t, J=54.3 Hz, 1H); ¹⁹F NMR (282MHz, CDCl₃) δ ppm: −63.29 (s, 3F), −73.18 (s, 3F), −109.22 (d, J=54.1Hz, 2F); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 149.3, 140.0 (t, ³J=6.1 Hz),137.6, 134.3 (t, ²J=22.6 Hz), 132.6 (t, ⁴J=1.2 Hz), 132.5, 131.4 (q,²J=32.5 Hz), 129.3, 126.1, 126.0 (q, ³J=3.8 Hz), 125.5 (q, ³J=3.7 Hz),123.7 (q, ¹J=270.7 Hz), 119.2 (t, ³J=6.0 Hz), 118.8 (q, ¹J=318.8 Hz),111.6 (t, ¹J=237.4 Hz); HRMS (EI) m/z: calcd for C₁₅H₈F₈O₃S: 420.0066.found: 420.0030.

Example 37 ethyl(E)-3-[4″-(benzyloxy)-2′-(difluoromethyl)-3-methyl-(1,1%4′,1″)terphenyl-2″-yl]acrylate(18a)

Yield 67% (hexane/AcOEt 20:1). ¹H RMN (300 MHz, CDCl₃) δ ppm: 7.66 (d,J=15.9 Hz, 2H), 7.43-7.19 (m, 10H), 7.19-7.08 (m, 3H), 7.01 (dd, J₁=8.3Hz, J₂=2.3 Hz, 1H), 6.51 (t, J=54.9 Hz, 1H), 6.32 (d, J=15.9 Hz, 1H),5.06 (s, 2H), 4.13 (q, J=7.1 Hz, 2H), 2.34 (s, 3H), 1.20 (t, J=7.2 Hz,3H); ¹⁹F RMN (282 MHz, CDCl₃) δ ppm: −107.9 (d, J=54.7 Hz, 2F); ¹³C RMN(75 MHz, CDCl₃) δ ppm: 166.6, 158.4, 143.2, 140.3, 139.1, 138.2, 136.5,134.6, 133.8, 131.9, 131.7 (t, ²J=22.1 Hz), 131.7, 130.2, 130.1, 128.7(2×), 128.3, 128.1, 127.5 (2×), 126.9 (t, ³J=4.8 Hz), 126.5, 119.9,117.0, 113.0 (t, ¹J=234.7 Hz), 112.5, 70.2, 60.5, 21.4, 14.2; HRMS (EI)m/z: calcd for C₃₂H₂₈F₂O₃: 498.2007. found: 498.1991; white solid, mp:124-126° C.

Example 38 ethyl(E)-3-[4″-(benzyloxy)-2′-(difluoromethyl)-3-(trifluoromethyl)-(1,1%4′,1″)terphenyl-2″-yl]acrylate(18b)

Yield 70% (hexane/AcOEt 20:1). ¹H RMN (300 MHz, CDCl₃) δ ppm: 7.65 (d,J=13.2 Hz, 4H), 7.59-7.50 (m, 2H), 7.44-7.23 (m, 8H), 7.19 (d, J=2.4 Hz,1H), 7.04 (dd, J₁=8.4 Hz, J₂=2.4 Hz, 1H), 6.45 (t, J=54.8 Hz, 1H), 6.34(d, J=15.6 Hz, 1H), 5.09 (s, 2H), 4.16 (q, J=7.1 Hz, 2H), 1.23 (t, J=7.1Hz, 3H); ¹⁹F RMN (282 MHz, CDCl₃) δ ppm: −63.16 (s, 3F), −108.1 (d,J=54.7 Hz, 2F); ¹³C RMN (75 MHz, CDCl₃) δ ppm: 166.6, 158.6, 143.0,140.1, 139.1, 138.5 (t, ³J=5.5 Hz), 136.5, 134.3, 133.8, 132.8, 132.2,131.8 (t, ²J=22.3 Hz), 131.7, 131.0 (q, ²J=32.6 Hz), 130.2, 129.0, 128.7(2×), 128.2, 127.5 (2×), 127.2 (t, ³J=5.2 Hz), 126.2 (q, ³J=3.8 Hz),124.8 (q, ³J=3.8 Hz), 123.9 (q, ¹J=272.4 Hz), 120.1, 117.0, 112.8 (t,¹J=237.2 Hz), 112.6, 70.3, 60.5, 14.2; HRMS (EI) m/z: calcd forC₃₂H₂₅F₅O₃: 552.1724. found: 552.1725.

Example 39 (E)-ethyl3-[4-(benzyloxy)-3′-(difluoromethyl)-4′-(pyridin-3-yl)biphenyl-2-yl]acrylate(18c)

Yield 55% (CH₂Cl₂/AcOEt 10:1). ¹H RMN (300 MHz, CDCl₃) δ ppm: 8.70 (dd,J=4.7 Hz, 1.6 Hz, 2H), 7.77 (ddd, J₁=7.8 Hz, J₂=2.1 Hz, J₃=1.8 Hz, 2H),7.72 (d, J=15.9 Hz, 1H), 7.51-7.34 (m, 9H), 7.32 (d, J=2.6 Hz, 1H), 7.11(dd, J₁=8.5 Hz, J₂=2.6 Hz, 1H), 6.54 (t, J=54.7 Hz, 1H), 6.42 (d, J=15.9Hz, 1H), 5.16 (s, 2H), 4.22 (q, J=7.1 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H);¹⁹F RMN (282 MHz, CDCl₃) δ ppm: −107.99 (d, J=54.7 Hz, 2F); ¹³C RMN (75MHz, CDCl₃) δ ppm: 166.6, 158.6, 149.8, 149.2, 143.0, 140.2, 139.2,136.8, 136.5, 136.3 (t, ³J=5.7 Hz), 134.2, 133.8, 132.2, 132.1 (t,²J=21.9 Hz), 131.7, 130.4, 128.7, 128.2, 127.5, 127.3 (t, ³J=5.6 Hz),123.2, 120.2, 117.0, 114.0, 112.8 (t, ¹J=237.5 Hz), 112.6, 70.2, 60.5,14.2; HRMS (EI) m/z: calcd for C₃₀H₂₅F₂NO₃. found. yellowish solid, mp:93-95° C.

Example 40 ethyl3-[2′-(difluoromethyl)-4″-hydroxy-3-methyl-(1,1′;4′,1″)terphenyl-2″-yl]propionate(19a)

Yield 98%. ¹H RMN (300 MHz, CDCl₃) δ ppm: 7.61 (s, 1H), 7.34 (d, J=8.1Hz, 1H), 7.25 (t, J=7.4 Hz, 2H), 7.20-7.08 (m, 3H), 7.05 (d, J=8.4 Hz,1H), 6.75 (d, J=1.8 Hz, 1H), 6.70 (dd, J₁=7.7 Hz, J₂=2.0 Hz, 1H), 6.51(t, J=54.9 Hz, 1H), 6.10 (s, 1H), 4.01 (q, J=7.3 Hz, 2H), 2.84 (t, J=7.8Hz, 2H), 2.42 (t, J=7.8 Hz, 2H), 2.34 (s, 3H), 1.12 (t, J=7.1 Hz, 3H);¹⁹F RMN (282 MHz, CDCl₃) δ ppm: −107.8 (d, J=54.7 Hz, 2F); ¹³C RMN (75MHz, CDCl₃) δ ppm: 173.4, 155.6, 140.8, 139.9 (t, ³J=6.2 Hz), 139.4,138.3, 138.1, 133.2, 131.6, 131.5 (t, ²J=21.7 Hz), 131.4, 130.2, 130.1,128.6, 128.3, 126.5, 126.4 (t, ²J=5.0 Hz), 115.8, 113.5 (t, ¹J=234.6Hz), 113.1, 60.7, 35.3, 28.3, 21.4, 14.0; HRMS (EI) m/z: calcd forC₂₅H₂₄F₂O₃: 410.1694. found: 410.1706.

Example 41 ethyl3-[2′-(difluoromethyl)-4″-hydroxy-3-(trifluoromethyl)-(1,1′;4′,1″)terphenyl-2″-yl]propionate(19b)

Yield 97%. ¹H RMN (300 MHz, CDCl₃) δ ppm: 7.62 (d, J=5.6 Hz, 3H), 7.52(d, J=4.4 Hz, 2H), 7.34 (dd, J₁=30.1 Hz, J₂=7.9 Hz, 2H), 7.04 (d, J=8.1Hz, 1H), 6.75 (d, J=1.8 Hz, 1H), 6.71 (dd, J₁=8.3 Hz, J₂=1.8 Hz, 1H),6.43 (t, J=54.9 Hz, 1H), 4.01 (q, J=7.1 Hz, 2H), 2.86 (t, J=7.7 Hz, 2H),2.42 (t, J=7.7 Hz, 2H), 1.12 (t, J=7.1 Hz, 3H); ¹⁹F RMN (282 MHz, CDCl₃)δ ppm: −63.1 (s, 3F), −107.9 (d, J=54.8 Hz, 2F); ¹³C RMN (75 MHz, CDCl₃)δ ppm: 173.4, 155.8, 141.7, 139.3, 139.2, 138.1 (t, ³J=6.0 Hz), 132.8,131.7, 131.6 (t, ²J=22.0 Hz), 131.5, 131.0 (q, ²J=32.4 Hz), 130.2,128.9, 126.8 (t, ³J=5.1 Hz), 126.2 (q, ³J=3.8 Hz), 124.7 (q, ³J=3.8 Hz),123.9 (q, ¹J=272.6 Hz), 115.8, 113.6, 112.9 (t, ¹J=236.9 Hz), 60.8,35.3, 28.3, 14.0; HRMS (EI) m/z: calcd for C₂₅H₂₁F₅O₃: 464.1411. found:464.1424.

Example 42 ethyl3-[3′-(difluoromethyl)-4-hydroxy-4′-(pyridin-3-yl)biphenyl-2-yl]propionate(19c)

Yield 65% (CH₂Cl₂/AcOEt 4:1). ¹H RMN (300 MHz, CDCl₃) δ ppm: 8.70 (dd,J₁=4.9 Hz, J₂=1.6 Hz, 2H), 7.83 (ddd, J₁=7.8 Hz, J₂=2.1 Hz, J₃=1.8 Hz,2H), 7.72 (br s, 1H), 7.53-7.45 (m, 2H), 7.37 (d, J=7.9 Hz, 1H), 7.12(d, J=8.2 Hz, 1H), 6.87 (d, J=2.5 Hz, 1H), 6.82 (dd, J₁=8.2 Hz, J₂=2.6Hz, 1H), 6.53 (t, J=54.8 Hz, 1H), 4.07 (q, J=7.1 Hz, 2H), 2.93 (t, J=7.8Hz, 2H), 2.49 (t, J=7.8 Hz, 2H), 1.19 (t, J=7.1 Hz, 3H); ¹⁹F RMN (282MHz, CDCl₃) δ ppm: −107.7 (d, J=54.8 Hz, 2F); ¹³C RMN (75 MHz, CDCl₃) δppm: 172.9, 156.6, 149.2, 148.5, 142.2, 139.4, 137.5, 135.3 (t, ³J=5.7Hz), 134.9, 132.2, 131.9 (t, ²J=23.1 Hz), 131.5, 130.4, 127.1 (t, ³J=5.4Hz), 123.5, 116.0, 113.7, 113.0 (t, ¹J=236.1 Hz), 60.5, 35.3, 28.2,14.1.

Example 433-[2′-(difluoromethyl)-4″-hydroxy-3-methyl-(1,1′;4′,1″)terphenyl-2″-yl]propionicacid (20a)

Yield 99%. ¹H RMN (300 MHz, CDCl₃) δ ppm: 7.60 (s, 1H), 7.32 (t, J=8.1Hz, 2H), 7.26 (d, J=7.2 Hz, 1H), 7.20-7.08 (m, 3H), 7.06 (d, J=8.1 Hz,1H), 6.74 (s, 1H), 6.70 (d, J=8.1 Hz, 1H), 6.51 (t, J=54.9 Hz, 1H), 2.86(t, J=7.5 Hz, 2H), 2.45 (t, J=7.7 Hz, 2H), 2.34 (s, 3H); ¹⁹F RMN (282MHz, CDCl₃) δ ppm: −107.81 (d, J=55.0 Hz, 2F); ¹³C RMN (75 MHz, CDCl₃) δppm: 178.4, 155.3, 140.7, 140.0 (t, ³J=6.2 Hz), 139.1, 138.3, 138.2,133.4, 131.7, 131.6 (t, ²J=21.6 Hz), 131.4, 130.2, 130.1, 128.6, 128.3,126.6, 126.4 (t, ²J=4.9 Hz), 115.7, 113.6, 113.1 (t, ¹J=234.6 Hz), 34.9,27.9, 21.4; HRMS (EI) m/z: calcd for C₂₃H₂₀F₂O₃: 382.1381. found:382.1377; white solid, mp: 40-42° C.

Example 443-[2′-(difluoromethyl)-4″-hydroxy-3-(trifluoromethyl)-(1,1′;4′,1″)terphenyl-2″-yl]propionicacid (20b)

Yield 98%. ¹H RMN (300 MHz, CDCl₃) δ ppm: 7.76-7.57 (m, 5H), 7.41 (dd,J₁=27.2 Hz, J₂=7.9 Hz, 2H), 7.13 (d, J=8.2 Hz, 1H), 6.84 (d, J=2.5 Hz,1H), 6.79 (dd, J₁=8.2 Hz, J₂=2.6 Hz, 1H), 6.51 (t, J=54.8 Hz, 1H), 2.94(t, J=7.6 Hz, 2H), 2.54 (t, J=7.6 Hz, 2H); ¹⁹F RMN (282 MHz, CDCl₃) δppm: −63.1 (s, 3F), −108.0 (d, J=54.8 Hz, 2F); ¹³C RMN (75 MHz, CDCl₃) δppm: 178.5, 155.5, 141.6, 139.2, 139.1, 138.2 (t, ³J=6.2 Hz), 133.1,132.8, 131.6 (t, ²J=22.0 Hz), 131.6, 131.0 (q, ²J=32.5 Hz), 130.3,128.9, 126.8 (t, ³J=5.3 Hz), 126.2 (q, ³J=3.3 Hz), 124.7 (q, ³J=3.3 Hz),123.9 (q, ¹J=272.3 Hz), 115.8, 113.7, 112.9 (t, ¹J=237.0 Hz), 34.8,27.9; HRMS (EI) m/z: calcd for C₂₃H₁₇F₅O₃: 435.1020 (M−1). found:435.1029; white solid, mp: 131-133° C.

Example 453-[3′-(difluoromethyl)-4-hydroxy-4′-(pyridin-3-yl)biphenyl-2-yl]propionicacid (20c)

Yield 97%. ¹H RMN (300 MHz, MeOD) δ ppm: 8.60 (dd, J₁=4.7 Hz, J₂=1.3 Hz,1H), 7.90 (ddd, J₁=8.1 Hz, J₂=2.1 Hz, J₃=1.8 Hz, 2H), 7.65 (br s, 1H),7.58-7.50 (m, 2H), 7.43 (d, J=7.8 Hz, 1H), 7.06 (d, J=8.3 Hz, 1H), 6.81(d, J=2.4 Hz, 1H), 6.73 (dd, J₁=8.3, J₂=2.6 Hz, 1H), 6.66 (t, J=54.8 Hz,1H), 2.87 (t, J=8.0 Hz, 2H), 2.44 (t, J=7.8 Hz, 2H); ¹⁹F RMN (282 MHz,MeOD) δ ppm: −107.9 (d, J=54.8 Hz, 2F); ¹³C RMN (75 MHz, MeOD) δ ppm:176.5, 158.6, 150.2, 149.5, 143.9, 140.7, 139.1, 136.9 (t, ³J=5.0 Hz),133.4 (t, ²J=21.7 Hz), 133.2, 133.1, 132.3, 132.0, 128.3 (t, ³J=6.1 Hz),125.0, 116.8, 115.1 (t, ¹J=236.5 Hz), 114.6, 36.2, 29.5; white solid,mp: 211-213° C.

Example 46 ethyl3-[4″-methoxy-3,2′-dimethyl-(1,1′;4′,1″)terphenyl-2″-yl]propionate (21b)

Yield 75% (hexane/AcOEt 10:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.25 (t,J=7.5 Hz, 1H), 7.20-7.04 (m, 7H), 6.78 (d, J=2.7 Hz, 1H), 6.74 (dd,J₁=8.1 Hz, J₂=2.7 Hz, 1H), 4.02 (q, J=7.1 Hz, 2H), 3.78 (s, 3H), 2.91(t, J=8.0 Hz, 2H), 2.42 (t, J=8.0 Hz, 2H), 2.34 (s, 3H), 2.24 (s, 3H),1.14 (t, J=7.2 Hz, 3H); ¹³C RMN (75 MHz, CDCl₃) δ ppm: 172.9, 158.9,141.6, 140.4, 140.0, 139.4, 137.6, 135.0, 134.4, 131.3, 131.3, 130.0,129.6, 127.9, 127.5, 126.7, 126.3, 114.5, 111.5, 60.4, 55.3, 35.5, 28.6,21.5, 20.6, 14.2; HRMS (EI) m/z: calcd for C₂₆H₂₈O₃: 388.2038. found:388.2042.

Example 47 ethyl3-[2′-(fluoromethyl)-4″-metoxy-3-methyl-(1,1′;4′,1″)terphenyl-2″-yl]propionate(21c)

Yield 70% (hexane/AcOEt 20:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.40 (s,1H), 7.31-7.23 (m, 3H), 7.15 (s, 2H), 7.11 (d, J=8.2 Hz, 2H), 6.79 (d,J=2.6 Hz, 1H), 6.75 (dd, J₁=8.3 Hz, J₂=2.6 Hz, 1H), 5.25 (d, J=48.0 Hz,2H), 4.00 (q, J=7.1 Hz, 2H), 3.76 (s, 3H), 2.89 (t, J=8.0 Hz, 2H), 2.41(t, J=8.0 Hz, 2H), 2.34 (s, 3H), 1.13 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282MHz, CDCl₃) δ ppm: −201.04 (t, J=48.0 Hz, 1F); ¹³C NMR (75 MHz, CDCl₃) δppm: 172.8, 159.1, 140.6 (d, ³J=4.5 Hz), 140.5, 139.7, 139.4, 137.9,133.7, 133.2 (d, ²J=15.9 Hz), 131.3, 130.5, 130.4, 130.0, 129.9, 129.8,128.1 (d, ³J=3.4 Hz), 126.3, 114.5, 111.6, 82.8 (d, ¹J=164.1), 60.4,55.3, 35.4, 28.5, 21.5, 14.1; HRMS (EI) m/z: calcd for C₂₆H₂₇FO₃:406.1944. found: 406.1921.

Example 48 ethyl3-[2′-(difluoromethyl)-4″-metoxy-3-methyl-(1,1%4′,1″)terphenyl-2″-yl]propionate(21d)

Yield 68% (hexane/AcOEt 20:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.62 (s,1H), 7.36 (d, J=8.0 Hz, 1H), 7.31 (s, 1H), 7.27 (d, J=7.4 Hz, 1H), 7.15(t, J=8.7 Hz, 3H), 7.12 (d, J=8.3 Hz, 1H), 6.80 (d, J=2.6 Hz, 1H), 6.77(dd, J₁=8.3 Hz, J₂=2.6 Hz, 1H), 6.52 (t, J=54.9 Hz, 1H), 4.01 (q, J=7.1Hz, 2H), 3.78 (s, 3H), 2.89 (t, J=7.9 Hz, 2H), 2.43 (t, J=7.9 Hz, 2H),2.36 (s, 3H), 1.13 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, CDCl₃) δ ppm:−107.87 (d, J=55.0 Hz, 2F); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 172.7, 159.3,140.8, 139.9 (t, ³J=6.6 Hz), 139.4, 138.3, 138.1, 133.3, 131.5 (t,²J=21.5 Hz), 131.3, 130.2, 130.1, 128.6, 128.3, 126.6, 126.4 (t, ³J=5.0Hz), 114.6, 113.1 (t, ¹J=234.6 Hz), 111.7, 60.4, 55.3, 35.4, 28.4, 21.4,14.1; HRMS (EI) m/z: calcd for C₂₆H₂₆F₂O₃: 424.1850. found: 424.1820.

Example 49 ethyl3-[2′-(hydroxymethyl)-4″-metoxy-3-(trifluoromethyl)-(1,1%4′,1″)terphenyl-2″-yl]propionate(21e)

Yield 76% (hexane/AcOEt 10:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.73 (s,1H), 7.65 (t, J=6.5 Hz, 2H), 7.56 (d, J=7.4 Hz, 1H), 7.53 (s, 1H), 7.29(d, J=1.8 Hz, 2H), 7.20 (d, J=8.2 Hz, 1H), 6.86 (d, J=2.6 Hz, 1H), 6.83(dd, J₁=8.2 Hz, J₂=2.6 Hz, 1H), 4.61 (s, 2H), 4.08 (q, J=7.1 Hz, 2H),3.84 (s, 3H), 2.97 (t, J=8.0 Hz, 2H), 2.52 (t, J=8.0 Hz, 2H), 1.21 (t,J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, CDCl₃) δ ppm: −63.02 (s, 3F); ¹³C NMR(75 MHz, CDCl₃) δ ppm: 173.1, 159.1, 141.2, 141.1, 139.3, 138.2, 137.9,133.8, 132.6, 131.2, 130.6 (q, ²J=32.0 Hz), 129.9, 129.7, 128.7, 128.6,126.0 (q, ³J=3.7 Hz), 124.1 (q, ¹J=270.7 Hz), 124.0 (q, ³J=3.7 Hz),114.6, 111.7, 62.9, 60.5, 55.2, 35.5, 28.6, 14.1; HRMS (EI) m/z: calcdfor C₂₆H₂₅F₃O₄: 458.1705. found: 458.1685.

Example 50 ethyl3-[2′-methyl-4″-metoxy-3-(trifluoromethyl)-(1,1%4′,1″)terphenyl-2″-yl]propionate(21f)

Yield 74% (hexane/AcOEt 20:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.63-7.46(m, 4H), 7.23-7.11 (m, 4H), 6.83 (d, J=2.5 Hz, 1H), 6.78 (dd, J₁=8.3 Hz,J₂=2.7 Hz, 1H), 4.05 (q, J=7.1 Hz, 2H), 3.80 (s, 3H), 2.94 (t, J=8.0 Hz,2H), 2.46 (t, J=8.1 Hz, 2H), 2.26 (s, 3H), 1.17 (t, J=7.1 Hz, 3H); ¹⁹FNMR (282 MHz, CDCl₃) δ ppm: −63.01 (s, 3F); ¹³C NMR (75 MHz, CDCl₃) δppm: 172.8, 159.0, 142.4, 140.9, 139.3, 138.8, 135.0, 134.1, 132.6,132.6, 131.5, 131.2, 130.5 (q, ²J=32.2 Hz), 129.5, 128.5, 127.0, 126.0(q, ³J=3.7 Hz), 124.2 (q, ¹J=270.8 Hz), 123.6 (q, ³J=3.7 Hz), 114.5,111.6, 60.3, 55.2, 35.4, 28.5, 20.4, 14.1; HRMS (EI) m/z: calcd forC₂₆H₂₅F₃O₃: 465.1653 (M+Na). found: 465.1664.

Example 51 ethyl3-[2′-(fluoromethyl)-4″-metoxy-3-(trifluoromethyl)-(1,1%4′,1″)terphenyl-2″-yl]propionate(21g)

Yield 71% (hexane/AcOEt 20:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.62 (s,1H), 7.57 (d, J=7.7 Hz, 2H), 7.51 (d, J=7.5 Hz, 1H), 7.43 (s, 1H), 7.31(s, 2H), 7.11 (d, J=8.3 Hz, 1H), 6.80 (d, J=2.6 Hz, 1H), 6.76 (dd,J₁=8.3 Hz, J₂=2.6 Hz, 1H), 5.21 (d, J=48.0 Hz, 2H), 4.01 (q, J=7.1 Hz,2H), 3.77 (s, 3H), 2.89 (t, J=7.9 Hz, 2H), 2.42 (t, J=7.9 Hz, 2H), 1.13(t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, CDCl₃) δ ppm: −63.12 (s, 3H),−199.34 (t, J=48.0 Hz, 1F); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 172.7, 159.3,141.5, 140.6, 139.4, 139.2 (d, ³J=4.1 Hz), 133.4, 133.2 (d, ²J=15.8 Hz),131.3, 131.2, 131.1, 130.7 (q, ²J=32.1 Hz), 130.3 (d, ³J=3.5 Hz), 130.0,128.8, 126.1 (q, ³J=3.8 Hz), 124.3 (q, ³J=3.8 Hz), 124.1 (q, ¹J=270.7Hz), 114.6, 111.7, 82.6 (d, ¹J=164.9 Hz), 60.4, 55.3, 35.4, 28.5, 14.1;HRMS (EI) m/z: calcd for C₂₆H₂₄F₄O₃: 460.1662. found: 460.1690.

Example 52 ethyl3-[2′-(difluoromethyl)-4″-metoxy-3-(trifluoromethyl)-(1,1′;4′,1″)terphenyl-2″-yl]propionate(21 h)

Yield 73% (hexane/AcOEt 20:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.64 (s,1H), 7.62 (d, J=2.4 Hz, 2H), 7.54 (t, J=2.4 Hz, 2H), 7.41 (d, J=7.8 Hz,1H), 7.31 (d, J=7.8 Hz, 1H), 7.12 (d, J=8.1 Hz, 1H), 6.81 (d, J=2.6 Hz,1H), 6.78 (dd, J₁=8.1 Hz, J₂=2.6 Hz, 1H), 6.44 (t, J=54.8 Hz, 1H), 4.01(q, J=7.1 Hz, 2H), 3.78 (s, 3H), 2.88 (t, J=8.0 Hz, 2H), 2.43 (t, J=8.0Hz, 2H), 1.13 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, CDCl₃) δ ppm: −63.16(s, 3F), −108.04 (d, J=54.7 Hz, 2F); ¹³C NMR (75 MHz, CDCl₃) δ ppm:172.7, 159.4, 141.8, 139.4, 139.3, 138.1 (t, ³J=6.3 Hz), 133.0, 132.8,131.7, 131.6 (t, ²J=21.8 Hz), 131.3, 131.0 (q, ²J=32.2 Hz), 130.2,128.9, 126.8 (t, ³J=5.4 Hz), 126.2 (q, ³J=3.8 Hz), 124.7 (q, ³J=3.8 Hz),124.1 (q, ¹J=270.8 Hz), 114.7, 112.9 (t, ¹J=235.6 Hz), 111.8, 60.5,55.3, 35.4, 28.4, 14.1; HRMS (EI) m/z: calcd for C₂₆H₂₃F₅O₃: 478.1567.found: 478.1513.

Example 53 ethyl3-[3′-(hydroxymethyl)-4-metoxy-4′-(pyridin-3-yl)biphenyl-2-yl]propionate(21i)

Terphenyl 28 (102 mg, 0.26 mmol) was dissolved in dry ethanol (10 mL)and the resulting solution cooled with an ice bath. Then, sodiumborohydride (1.5 equiv) was slowly added and the reaction mixture wasstirred for 30 min at room temperature. The reaction was hydrolyzed withwater (1 mL), and ethanol was removed under reduced pressure. Theaqueous layer was extracted with AcOEt, and the combined organic layerswere dried over Na₂SO₄, filtered and removed in vacuo under reducedpressure. The crude reaction product was purified by means ofchromatography on silica gel (CH₂Cl₂/AcOEt 1:1) to obtain 74 mg of 21i.Yield 72%. ¹H NMR (300 MHz, CDCl₃) δ ppm: 8.56 (d, J=1.8 Hz, 1H), 8.48(dd, J₁=4.8 Hz, J₂=1.8 Hz, 1H), 7.75 (dt, J₁=7.8 Hz, J₂=1.8 Hz, 1H),7.47 (br s, 1H), 7.28 (dd, J₁=7.5 Hz, J₂=4.2 Hz, 1H), 7.22 (br s, 2H),7.11 (d, J=8.4 Hz, 1H), 6.78 (d, J=2.4 Hz, 1H), 6.75 (dd, J₁=8.1 Hz,J₂=2.7 Hz, 1H), 4.54 (br s, 2H), 3.99 (q, J=7.2 Hz, 2H), 3.76 (s, 3H),2.88 (t, J=8.1 Hz, 2H), 2.43 (t, J=8.0 Hz, 2H), 1.12 (t, J=7.2 Hz, 3H);¹³C NMR (75 MHz, CDCl₃) δ ppm: 173.0, 159.0, 149.6, 148.2, 141.4, 139.3,138.4, 136.8, 136.2, 135.8, 133.7, 131.2, 130.0, 129.9, 128.7, 123.1,114.6, 111.6, 62.6, 60.5, 55.2, 35.5, 28.5, 14.1; HRMS (EI) m/z: calcdfor C₂₄H₂₅NO₄: 391.1784. found: 391.1768.

Example 54 ethyl3-[4-methoxy-3′-methyl-4′-(pyridin-3-yl)biphenyl-2-yl]propionate (21j)

Yield 30% (CH₂Cl₂/AcOEt 20:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 8.66 (d,J=1.5 Hz, 1H), 8.61 (dd, J₁=4.8 Hz, J₂=1.4 Hz, 1H), 7.71 (ddd, J₁=7.8Hz, J₂=2.2 Hz, J₃=1.7 Hz, 1H), 7.37 (ddd, J₁=7.8 Hz, J₂=4.8 Hz, J₃=0.8Hz, 1H), 7.24-7.17 (m, 3H), 7.17 (d, J=8.4 Hz, 1H), 6.86 (d, J=2.4 Hz,1H), 6.82 (dd, J₁=8.3 Hz, J₂=2.7 Hz, 1H), 4.09 (q, J=7.1 Hz, 2H), 3.84(s, 3H), 2.97 (t, J=8.0 Hz, 2H), 2.49 (t, J=8.0 Hz, 2H), 2.31 (s, 3H),1.21 (t, J=7.1 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 172.8, 159.0,150.0, 148.1, 141.1, 139.3, 137.2, 136.5, 135.4, 134.0, 131.6, 131.3,129.7, 127.1, 123.0, 114.5, 111.6, 60.4, 55.3, 35.4, 28.5, 20.4, 14.2.

Example 55 ethyl3-[3′-(fluoromethyl)-4-metoxy-4′-(pyridin-3-yl)biphenyl-2-yl]propionate(21k)

Yield 46% (CH₂Cl₂/AcOEt 5:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 8.69 (d,J=1.8 Hz, 1H), 8.66 (dd, J₁=4.8 Hz, J₂=1.2 Hz, 1H), 7.80 (dt, J₁=7.8 Hz,J₂=2.0 Hz, 1H), 7.51 (s, 1H), 7.35-7.43 (m, 3H), 7.18 (d, J=8.1 Hz, 1H),6.87 (d, J=2.4 Hz, 1H), 6.84 (dd, J₁=8.4 Hz, J₂=2.7 Hz, 1H), 5.29 (d,J=48.0 Hz, 2H), 4.08 (q, J=7.1 Hz, 2H), 3.84 (s, 3H), 2.96 (t, J=8.0 Hz,2H), 2.49 (t, J=8.0 Hz, 2H), 1.20 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz,CDCl₃) δ ppm: −198.37 (t, J=48.8 Hz, 1F); ¹³C NMR (75 MHz, CDCl₃) δ ppm:172.7, 159.2, 149.8, 148.8, 141.6, 139.3, 137.0 (d, ³J=3.8 Hz), 136.7,136.6, 135.4, 133.3 (d, ²J=15.8 Hz), 131.4, 131.3, 130.4 (d, ³J=3.5 Hz),130.1, 123.1, 114.5, 111.7, 85.1 (d, ¹J=164.9 Hz), 60.4, 55.3, 35.4,28.4, 14.1; HRMS (EI) m/z: calcd for C₂₄H₂₄FNO₃: 393.1740. found:393.1713.

Example 56 ethyl3-[3′-(difluoromethyl)-4-metoxy-4′-(pyridin-3-yl)biphenyl-2-yl]propionate(21l)

Yield 43% (CH₂Cl₂/AcOEt 10:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 8.69 (dd,J₁=4.7 Hz, J₂=1.7 Hz, 2H), 7.76 (dt, J₁=7.8 Hz, J₂=2.0 Hz, 1H), 7.72 (brs, 1H), 7.50 (d, J=7.8 Hz, 1H), 7.42 (dd, J₁=8.0 Hz, J₂=5.6 Hz, 1H),7.38 (d, J=7.8 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 6.88 (d, J=2.7 Hz, 1H),6.85 (dd, J₁=8.3 Hz, J₂=2.6 Hz, 1H), 6.53 (t, J=54.9 Hz, 1H), 4.08 (q,J=7.2 Hz, 2H), 3.85 (s, 3H), 2.96 (t, J=8.0 Hz, 2H), 2.50 (t, J=7.8 Hz,2H), 1.20 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, CDCl₃) δ ppm: −107.88 (d,J=56.1 Hz, 2F); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 172.6, 159.4, 149.9,149.2, 141.9, 139.3, 136.8, 135.8 (t, ³J=5.8 Hz), 134.3, 132.9, 131.9(t, ²J=21.9 Hz), 131.8, 131.3, 130.4, 126.9 (t, ³J=5.4 Hz), 123.1,114.6, 112.9 (t, ¹J=235.8 Hz), 111.8, 60.4, 55.3, 35.4, 28.4, 14.1; HRMS(EI) m/z: calcd for C₂₄H₂₃F₂NO₃: 411.1646. found: 411.1658.

Example 573-[2′-(hydroxymethyl)-4″-methoxy-3-methyl-(1,1′;4′,1″)terphenyl-2″-yl]propionicacid (22a)

Yield 97%. ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.39 (d, J=1.5 Hz, 1H),7.28-7.14 (m, 5H), 7.12 (t, J=3.1 Hz, 2H), 6.80-6.72 (m, 2H), 4.58 (s,2H), 3.77 (s, 3H), 2.89 (t, J=7.9 Hz, 2H), 2.47 (t, J=7.9 Hz, 2H), 2.33(s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 177.5, 159.0, 140.3, 140.3,139.8, 139.0, 137.9, 137.7, 134.1, 131.3, 129.9, 129.3, 128.5, 128.1,128.0, 126.2, 114.6, 111.7, 63.1, 55.3, 35.2, 28.4, 21.5; HRMS (EI) m/z:calcd for C₂₄H₂₄O₄: 376.1674. found: 376.1657.

Example 583-[4″-methoxy-3,2′-dimethyl-(1,1′;4′,1″)terphenyl-2″-yl]propionic acid(22b)

Yield 99%. ¹H RMN (300 MHz, CDCl₃) δ ppm: 7.24 (t, J=7.5 Hz, 1H),7.19-7.02 (m, 7H), 6.80-6.70 (m, 2H), 3.76 (s, 3H), 2.90 (t, J=7.8 Hz,2H), 2.45 (t, J=7.8 Hz, 2H), 2.34 (s, 3H), 2.23 (s, 3H); ¹³C RMN (75MHz, CDCl₃) δ ppm: 178.5, 158.9, 141.6, 140.5, 139.9, 139.0, 137.6,135.1, 134.4, 131.4, 131.2, 130.0, 129.6, 127.9, 127.5, 126.7, 126.3,114.5, 111.6, 55.3, 35.1, 28.3, 21.5, 20.6; HRMS (EI) m/z: calcd forC₂₄H₂₄O₃: 360.1725. found: 360.1727.

Example 593-[2′-(fluoromethyl)-4″-methoxy-3-methyl-(1,1′;4′,1″)terphenyl-2″-yl]propionicacid (22c)

Yield 99%. ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.47 (s, 1H), 7.39-7.30 (m,3H), 7.25-7.18 (m, 4H), 6.79 (d, J=2.6 Hz, 1H), 6.76 (dd, J₁=8.2 Hz,J₂=2.6 Hz, 1H), 5.25 (d, J=48.0 Hz, 2H), 3.76 (s, 3H), 2.90 (t, J=7.9Hz, 2H), 2.46 (t, J=7.9 Hz, 2H), 2.34 (s, 3H); ¹⁹F NMR (282 MHz, CDCl₃)δ ppm: −201.25 (t, J=47.9 Hz, 1F); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 178.1,159.2, 140.7 (d, ³J=4.4 Hz), 140.5, 139.7, 139.0, 138.0, 133.8, 133.3(d, ²J=15.9 Hz), 131.4, 130.5, 130.4, 130.0, 129.9, 129.8, 128.2 (d,³J=4.9 Hz), 126.4, 114.6, 111.8, 82.8 (d, ¹J=164.3 Hz), 55.3, 35.0,28.3, 21.5; HRMS (EI) m/z: calcd for C₂₄H₂₃FO₃: 378.1631. found:378.1637.

Example 603-[2′-(difluoromethyl)-4″-methoxy-3-methyl-(1,1′;4′,1″)terphenyl-2″-yl]propionicacid (22d)

Yield 98%. ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.64 (s, 1H), 7.37 (d, J=7.8Hz, 1H), 7.30 (t, J=7.8 Hz, 2H), 7.19 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.4Hz, 2H), 6.82 (d, J=2.4 Hz, 1H), 6.80 (dd, J₁=8.1 Hz, J₂=2.4 Hz, 1H),6.54 (t, J=54.9 Hz, 1H), 3.79 (s, 3H), 2.91 (t, J=7.8 Hz, 2H), 2.49 (t,J=7.8 Hz, 2H), 2.38 (s, 3H); ¹⁹F NMR (282 MHz, CDCl₃) δ ppm: −107.88 (d,J=55.9 Hz, 2F); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 178.7, 159.3, 140.7,140.0 (t, ³J=6.3 Hz), 139.0, 138.3, 138.1, 133.4, 131.6 (t, ²J=20.4 Hz),131.4, 131.3 (2×), 130.2, 130.1, 128.6, 128.3, 126.6, 126.4 (t, ³J=4.8Hz), 114.6, 113.1 (t, ¹J=234.7 Hz), 111.8, 55.3, 35.0, 28.1, 21.4; HRMS(EI) m/z: calcd for C₂₄H₂₂F₂O₃: 396.1537. found: 396.1527.

Example 613-[2′-(hydroxymethyl)-4″-methoxy-3-(trifluoromethyl)-(1,1′;4′,1″)terphenyl-2″-yl]propionicacid (22e)

Yield 98%. ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.63 (s, 1H), 7.57 (d, J=7.5Hz, 2H), 7.47 (t, J=7.6 Hz, 1H), 7.42 (s, 1H), 7.26-7.19 (m, 2H), 7.12(d, J=7.9 Hz, 1H), 6.78 (d, J=2.6 Hz, 1H), 6.76 (dd, J₁=8.0 Hz, J₂=2.6Hz, 1H), 4.53 (s, 2H), 3.77 (s, 3H), 2.89 (t, J=7.9 Hz, 2H), 2.47 (t,J=7.9 Hz, 2H); ¹⁹F NMR (282 MHz, CDCl₃) δ ppm: −63.05 (s, 3F); ¹³C NMR(75 MHz, CDCl₃) δ ppm: 177.5, 159.2, 141.3, 141.2, 139.0, 138.3, 137.7,133.8, 132.6, 131.3, 130.7 (q, ²J=32.1 Hz), 130.0, 129.8, 128.9, 128.7,126.0 (q, ³J=3.8 Hz), 124.1 (q, ¹J=270.6 Hz), 124.0 (q, ³J=3.8 Hz),114.7, 111.8, 62.9, 55.3, 35.2, 28.4; HRMS (EI) m/z: calcd forC₂₄H₂₁F₃O₄: 430.1392. found: 430.1314.

Example 623-[2′-methyl-4″-methoxy-3-(trifluoromethyl)-(1,1′;4′,1″)terphenyl-2″-yl]propionicacid (22f)

Yield 99%. ¹H RMN (300 MHz, CDCl₃) δ ppm: 7.70-7.52 (m, 4H), 7.28-7.16(m, 4H), 6.88 (d, J=2.4 Hz, 1H), 6.85 (dd, J₁=8.2 Hz, J₂=2.7 Hz, 1H),3.85 (s, 3H), 3.00 (t, J=8.0 Hz, 2H) 2.55 (t, J=8.0 Hz, 2H), 2.31 (s,3H); ¹⁹F NMR (282 MHz, CDCl₃) δ ppm: −63.02 (s, 3F); ¹³C RMN (75 MHz,CDCl₃) δ ppm: 178.9, 159.0, 142.4, 140.8, 138.9, 138.9, 135.1, 134.1,132.6, 131.5, 131.4, 130.5 (q, ²J=32.1 Hz), 129.6, 128.5, 127.0, 126.0(q, ³J=3.8 Hz), 124.2 (q, ¹J=270.8 Hz), 123.6 (q, ³J=3.5 Hz), 114.6,111.7, 55.3, 35.1, 28.2, 20.4; HRMS (EI) m/z: calcd for C₂₄H₂₁F₃O₃:413.1365 (M−1). found: 413.1366.

Example 633-[2′-(fluoromethyl)-4″-methoxy-3-(trifluoromethyl)-(1,1′;4′,1″)terphenyl-2″-yl]propionicacid (22g)

Yield 99%. ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.71 (s, 1H), 7.66 (s, 1H),7.63 (s, 1H), 7.58 (t, J=7.4 Hz, 1H), 7.50 (s, 1H), 7.38 (s, 2H), 7.19(d, J=8.2 Hz, 1H), 6.88 (d, J=2.5 Hz, 1H), 6.85 (dd, J₁=8.2 Hz, J₂=2.5Hz, 1H), 5.29 (d, J=47.9 Hz, 2H), 3.85 (s, 3H), 2.97 (t, J=7.9 Hz, 2H),2.55 (t, J=7.9 Hz, 2H); ¹⁹F NMR (282 MHz, CDCl₃) δ ppm: −63.09 (s, 3F),−199.50 (t, J=47.9 Hz, 1F); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 178.2, 159.3,141.4, 140.6, 139.3 (d, ³J=4.2 Hz), 139.0, 133.4, 133.2 (d, ²J=15.8 Hz),131.4, 131.1, 131.0, 130.8 (q, ²J=32.1 Hz), 130.2 (d, ³J=3.3 Hz), 130.0,128.8, 126.1 (q, ³J=3.8 Hz), 124.3 (q, ³J=3.8 Hz), 124.1 (q, ¹J=270.8Hz), 114.7, 111.8, 82.6 (d, ¹J=165.1 Hz), 55.3, 35.0, 28.2; HRMS (EI)m/z: calcd for C₂₄H₂₀F₄O₃: 432.1349. found: 432.1337.

Example 643-[2′-(difluoromethyl)-4″-methoxy-3-(trifluoromethyl)-(1,1′;4′,1″)terphenyl-2″-yl]propionicacid (22h)

Yield 98%. ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.60 (d, J=5.1 Hz, 3H), 7.49(d, J=5.4 Hz, 2H), 7.36 (d, J=7.8 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.08(d, J=8.1 Hz, 1H), 6.79-6.71 (m, 2H), 6.40 (t, J=54.8 Hz, 1H), 3.72 (s,3H), 2.83 (t, J=7.2 Hz, 2H), 2.41 (t, J=7.2 Hz, 2H); ¹⁹F NMR (282 MHz,CDCl₃) δ ppm: −63.15 (s, 3F), −108.02 (d, J=54.7 Hz, 2F); ¹³C NMR (75MHz, CDCl₃) δ ppm: 159.4, 141.7, 139.3, 138.1 (t, ³J=6.0 Hz), 133.0,132.8, 131.7, 131.7 (t, ²J=19.5 Hz), 131.3, 131.0 (q, ²J=32.4 Hz),130.2, 128.9, 126.8 (t, ³J=5.4 Hz), 126.2 (q, ³J=3.4 Hz), 124.7 (q,³J=3.9 Hz), 124.0 (q, ¹J=270.8 Hz), 114.7, 112.9 (t, ¹J=235.6 Hz),111.7, 55.3, 29.7, 28.3; HRMS (EI) m/z: calcd for C₂₄H₁₉F₅O₃: 450.1254.found: 450.1260.

Example 653-[3′-(hydroxymethyl)-4-methoxy-4′-(pyridin-3-yl)biphenyl-2-yl]propionicacid (22i)

Yield 76%. ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 8.66 (d, J=1.8 Hz, 1H), 8.59(dd, J₁=4.8 Hz, J₂=1.8 Hz, 1H), 7.91 (dt, J₁=7.8 Hz, J₂=2.0 Hz, 1H),7.50 (br s, 1H), 7.48 (dd, J₁=7.8 Hz, J₂=4.8 Hz, 1H), 7.33 (d, J=7.8 Hz,1H), 7.29 (dd, J₁=7.8 Hz, J₂=1.5 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 6.94(d, J=2.7 Hz, 1H), 6.86 (dd, J₁=8.4 Hz, J₂=2.7 Hz, 1H), 4.44 (br s, 2H),3.78 (s, 3H), 2.82 (t, J=7.7 Hz, 2H), 2.43 (t, J=8.0 Hz, 2H); ¹³C NMR(75 MHz, DMSO-d₆) δ ppm: 173.7, 158.6, 149.3, 148.1, 140.6, 139.6,139.4, 136.4, 135.6, 134.9, 133.4, 130.8, 129.4, 129.2, 127.8, 123.1,114.3, 111.4, 60.7, 55.0, 34.7, 27.8; HRMS (EI) m/z: calcd forC₂₂H₂₁NO₄: 363.1471. found: 363.1420; yellowish oil, mp: 174-176° C.

Example 663-[4-methoxy-3′-methyl-4′-(pyridin-3-yl)biphenyl-2-yl]propionic acid(22j)

Yield 96%. ¹H NMR (300 MHz, CDCl₃) δ ppm: 8.67 (s, 1H), 8.57 (d, J=3.7Hz, 1H), 7.77 (dd, J=7.8 Hz, 1.5 Hz, 1H), 7.42 (dd, J₁=7.8 Hz, J₂=4.9Hz, 1H), 7.24-7.16 (m, 3H), 7.16 (d, J=8.4 Hz, 1H), 6.88 (d, J=2.5 Hz,1H), 6.82 (dd, J₁=8.4 Hz, J₂=2.6 Hz, 1H), 3.84 (s, 3H), 2.97 (t, J=8.3Hz, 2H), 2.54 (t, J=8.3 Hz, 2H), 2.27 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δppm: 177.5, 159.1, 148.9, 146.6, 141.4, 139.6, 137.9, 137.6, 135.9,135.4, 134.0, 131.6, 131.1, 129.7, 127.2, 123.4, 114.5, 111.5, 55.3,35.7, 28.7, 20.4; HRMS (EI) m/z: calcd for C₂₂H₂₁NO₃: 348.1600 (M+1).found: 348.1595; white solid, mp: 153-155° C.

Example 673-[3′-(fluoromethyl)-4-methoxy-4′-(pyridin-3-yl)biphenyl-2-yl]propionicacid (22k)

Yield 89%. ¹H NMR (300 MHz, CDCl₃) δ ppm: 8.72 (s, 1H), 8.65 (s, 1H),7.87 (d, J=7.5 Hz, 1H), 7.45 (s, 1H), 7.33-7.47 (m, 3H), 7.19 (d, J=7.8Hz, 1H), 6.88 (d, J=2.4 Hz, 1H), 6.84 (dd, J₁=7.8 Hz, J₂=2.4 Hz, 1H),5.26 (d, J=48.3 Hz, 2H), 3.85 (s, 3H), 2.96 (t, J=7.5 Hz, 2H), 2.55 (t,J=7.2 Hz, 2H); ¹⁹F NMR (282 MHz, CDCl₃) δ ppm: −197.91 (t, J=48.1 Hz,1F); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 159.3, 148.8, 147.6, 141.9, 139.6,137.7, 136.6, 136.0, 133.3 (d, ²J=17.6 Hz), 133.2, 131.5 (d, ³J=5.7 Hz),131.2, 130.5, 130.2, 123.5, 114.6, 111.5, 82.5 (d, ¹J=164.5 Hz), 55.2,35.8, 28.6; HRMS (EI) m/z: calcd for C₂₂H₂₀FNO₃: 365.1427. found:365.1400; yellowish solid.

Example 683-[3′-(difluoromethyl)-4-methoxy-4′-(pyridin-3-yl)biphenyl-2-yl]propionicacid (22l)

Yield 86%. ¹H NMR (300 MHz, CDCl₃) δ ppm: 8.71 (s, 1H), 8.66 (d, J=4.5Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.69 (s, 1H), 7.48 (d, J=7.8 Hz, 1H),7.50 (dd, J₁=7.8 Hz, J₂=5.0 Hz, 1H), 7.34 (d, J=7.8 Hz, 1H), 7.18 (d,J=8.4 Hz, 1H), 6.89 (d, J=2.1 Hz, 1H), 6.83 (dd, J₁=8.4 Hz, J₂=2.4 Hz,1H), 6.49 (t, J=54.8 Hz, 1H), 3.84 (s, 3H), 2.94 (t, J=8.0 Hz, 2H), 2.54(t, J=8.1 Hz, 2H); ¹⁹F NMR (282 MHz, CDCl₃) δ ppm: −107.94 (d, J=54.7Hz, 2F); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 176.6, 159.4, 148.9, 147.9,142.1, 139.5, 137.8, 135.3 (t, ³J=5.6 Hz), 134.9, 132.9, 131.9 (t,²J=21.7 Hz), 131.2, 130.5, 127.0 (t, ³J=5.2 Hz), 123.5, 114.6, 113.0 (t,¹J=236.1 Hz), 111.7, 55.3, 35.5, 28.5; HRMS (EI) m/z: calcd forC₂₂H₁₉F₂NO₃: 383.1333. found: 383.1313; white solid.

Example 69 ethyl3-[3,2′-dimethyl-4″-propoxy-(1,1′;4′,1″)terphenyl-2″-yl]propionate (23a)

Yield 78% (hexane/AcOEt 10:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.28 (t,J=7.6 Hz, 1H), 7.21 (d, J=7.7 Hz, 1H), 7.18-7.08 (m, 6H), 6.82 (d, J=2.5Hz, 1H), 6.77 (dd, J₁=8.4 Hz, J₂=2.6 Hz, 1H), 4.05 (q, J=7.1 Hz, 2H),3.92 (t, J=6.6 Hz, 2H), 2.95 (t, J=8.0 Hz, 2H), 2.46 (t, J=8.0 Hz, 2H),2.38 (s, 3H), 2.28 (s, 3H), 1.80 (sex, J=7.1 Hz, 2H), 1.18 (t, J=7.1 Hz,3H), 1.03 (t, J=7.4 Hz, 3H); ¹³C RMN (75 MHz, CDCl₃) δ ppm: 172.9,158.4, 141.7, 140.3, 140.1, 139.3, 137.6, 135.0, 134.2, 131.3, 130.0,129.5, 127.9, 127.4, 126.7, 126.3, 115.1, 112.1, 69.5, 60.3, 35.5, 28.6,22.6, 21.5, 20.5, 14.2, 10.5; HRMS (EI) m/z: calcd for C₂₈H₃₂O₃:439.2249 (M+Na). found: 439.2245.

Example 70 ethyl3-[4″-(ethoxycarbonylmethoxy)-3,2′-dimethyl-(1,1;4′,1″)terphenyl-2″-yl]propionate(23b)

Yield 73% (hexane/AcOEt 7:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.32 (t,J=7.7 Hz, 1H), 7.27-7.11 (m, 7H), 6.88 (d, J=2.6 Hz, 1H), 6.80 (dd,J₁=8.4 Hz, J₂=2.7 Hz, 1H), 4.65 (s, 2H), 4.31 (q, J=7.1 Hz, 2H), 4.09(q, J=7.1 Hz, 2H), 2.97 (t, J=8.0 Hz, 2H), 2.48 (t, J=8.0 Hz, 2H), 2.42(s, 3H), 2.31 (s, 3H), 1.33 (t, J=7.1 Hz, 3H), 1.21 (t, J=7.1 Hz, 3H);¹³C NMR (75 MHz, CDCl₃) δ ppm: 172.8, 168.9, 157.1, 141.6, 140.5, 139.8,139.6, 137.6, 135.5, 135.1, 131.4, 131.2, 130.0, 129.6, 127.9, 127.5,126.7, 126.3, 115.4, 112.0, 65.5, 61.4, 60.4, 35.4, 28.5, 21.5, 20.5,14.2; HRMS (EI) m/z: calcd for C₂₉H₃₂O₅: 483.2147 (M+Na). found:483.2140.

Example 71 ethyl3-[2′-methyl-4″-propoxy-3-(trifluoromethyl)-(1,1′,4′,1″)terphenyl-2″-yl]propionate(23c)

Yield 75% (hexane/AcOEt 20:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.68-7.51(m, 4H), 7.25-7.17 (m, 3H), 7.16 (d, J=8.2 Hz, 1H), 6.86 (d, J=2.5 Hz,1H), 6.82 (dd, J₁=8.3 Hz, J₂=2.6 Hz, 1H), 4.09 (q, J=7.1 Hz, 2H), 3.96(t, J=6.6 Hz, 2H), 2.97 (t, J=8.1 Hz, 2H), 2.49 (t, J=8.1 Hz, 2H), 2.30(s, 3H), 1.84 (sex, J=7.1 Hz, 2H), 1.21 (t, J=7.1 Hz, 3H), 1.06 (t,J=7.4 Hz, 3H); ¹⁹F NMR (282 MHz, CDCl₃) δ ppm: −63.05 (s, 3F); ¹³C NMR(75 MHz, CDCl₃) δ ppm: 172.9, 158.6, 142.4, 141.0, 139.3, 138.7, 135.0,133.9, 132.6, 131.5, 131.2, 130.6 (q, ²J=31.9 Hz), 129.5, 128.6, 127.0,126.0 (q, ³J=3.8 Hz), 124.2 (q, ¹J=270.5 Hz), 123.6 (q, ³J=4.0 Hz),115.1, 112.1, 69.5, 60.4, 35.5, 29.7, 28.5, 22.6, 20.4, 14.2, 10.6.

Example 723-[3,2′-dimethyl-4″-propoxy-(1,1%4′,1″)terphenyl-2″-yl]propionic acid(24a)

Yield 99%. ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.35 (t, J=7.5 Hz, 1H), 7.28(d, J=7.7 Hz, 1H), 7.25-7.15 (m, 6H), 6.90 (d, J=2.5 Hz, 1H), 6.86 (dd,J₁=8.3 Hz, J₂=2.6 Hz, 1H), 3.99 (t, J=6.6 Hz, 2H), 3.02 (t, J=8.0 Hz,2H), 2.58 (t, J=8.0 Hz, 2H), 2.45 (s, 3H), 2.35 (s, 3H), 1.87 (sex,J=7.1 Hz, 2H), 1.10 (t, J=7.4 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ ppm:179.1, 158.5, 141.6, 140.4, 140.0, 138.8, 137.6, 135.1, 134.2, 131.3,131.2, 130.0, 129.6, 127.9, 127.4, 126.7, 126.3, 115.1, 112.2, 69.5,35.2, 28.2, 22.6, 21.4, 20.5, 10.5; HRMS (EI) m/z: calcd for C₂₆H₂₈O₃:387.1960 (M−1). found: 387.1955.

Example 733-[4″-(carboxymethoxy)-3,2′-dimethyl-(1,1′;4′1″)terphenyl-2″-yl]propionicacid (24b)

Yield 99%. ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.35 (t, J=7.5 Hz, 1H), 7.28(d, J=7.7 Hz, 1H), 7.25-7.13 (m, 6H), 6.94 (d, J=2.6 Hz, 1H), 6.86 (dd,J₁=8.4 Hz, J₂=2.6 Hz, 1H), 4.74 (s, 2H), 3.02 (t, J=7.7 Hz, 2H), 2.58(t, J=7.7 Hz, 2H), 2.45 (s, 3H), 2.34 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δppm: 179.4, 174.8, 156.7, 141.5, 140.6, 139.5, 139.2, 137.6, 135.7,135.2, 131.5, 131.1, 130.0, 129.6, 127.9, 127.5, 126.6, 126.3, 115.2,112.3, 64.8, 34.9, 28.1, 21.4, 20.5; HRMS (EI) m/z: calcd for C₂₅H₂₄O₅:403.1545 (M−1). found: 403.1543; white solid, mp: 130-132° C.

Example 743-[2′-methyl-4″-propoxy-3-(trifluoromethyl)-(1,1′;4′,1″)terphenyl-2″-yl]propionicacid (24c)

Yield 99%. ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.69-7.50 (m, 4H), 7.24-7.12(m, 4H), 6.86 (d, J=2.4 Hz, 1H), 6.82 (dd, J₁=8.3 Hz, J₂=2.6 Hz, 1H),3.96 (t, J=6.6 Hz, 2H), 2.97 (t, J=8.1 Hz, 2H), 2.54 (t, J=8.1 Hz, 2H),2.29 (s, 3H), 1.83 (sex, J=7.1 Hz, 2H), 1.06 (t, J=7.4 Hz, 3H); ¹⁹F NMR(282 MHz, CDCl₃) δ ppm: −63.03 (s, 3F); ¹³C NMR (75 MHz, CDCl₃) δ ppm:177.9, 158.6, 142.4, 140.9, 139.3, 138.8, 135.1, 133.9, 132.6, 131.5,131.3, 130.6 (q, ²J=31.8 Hz), 129.6, 128.5, 127.0, 126.1 (q, ³J=3.8 Hz),124.2 (q, ¹J=270.5 Hz), 123.6 (q, ³J=3.8 Hz), 115.1, 112.2, 69.6, 35.0,28.3, 22.6, 20.4, 10.5.

Example 75 ethyl 3-(3-methoxyphenyl)propionate (25)

A solution of 3-methoxyphenylsuccinic acid (1.500 g, 8.32 mmol) in dryethanol (15 mL) with a small quantity of DOWEX™ strong acid ion exchangeresin was refluxed for 22 h. The reaction mixture was filtered and thesolvent evaporated in vacuo to give 1.618 g of ester 25. Yield 93%. ¹HNMR (300 MHz, CDCl₃) δ ppm: 7.15 (q, J=8.6 Hz, 1H), 6.72 (d, J=7.8 Hz,1H), 6.65-6.70 (m, 2H), 4.06 (q, J=7.1 Hz, 2H), 3.72 (s, 3H), 2.86 (t,J=7.9 Hz, 2H), 2.54 (t, J=7.9 Hz, 2H), 1.17 (t, J=7.1 Hz, 3H); ¹³C NMR(75 MHz, CDCl₃) δ ppm: 172.9, 159.7, 142.2, 129.4, 120.6, 114.0, 111.6,60.4, 55.1, 35.8, 31.0, 14.2; HRMS (EI) m/z: calcd for C₁₂H₁₆O₃:208.1099. found: 208.1104.

Example 76 ethyl 3-(2-iodo-5-methoxyphenyl)propionate (26)

To a solution of n-butyltriphenylphosphonium bromide (7.188 g, 18.00mmol) in water/acetone (10:1, 200 mL) was added a solution of potassiumperoxodisulfate (2.433 g, 9.00 mmol) in water (50 mL), and the mixturewas stirred at room temperature for 15 min. The resulting white solidwas filtered, washed with cold distilled water and dried in a desiccatorover calcium chloride.

To a solution of ester 25 (1.618 g, 7.77 mmol) in acetonitrile (100 mL),iodine (1.972 g, 7.77 mmol) and n-butyltriphenylphosphoniumperoxodisulfate (6.455 g, 7.77 mmol) were added and refluxed for 45 min.The reaction mixture was cooled to room temperature and the excess ofiodine was removed by dropwise addition of 1M Na₂S₂O₃ solution. Thecolourless solution was transferred to a separatory funnel and theorganic layer was separated and dried over Na₂SO₄. Evaporation of thesolvent followed by means of column chromatography on silica gel(hexane/isopropylether 10:1) gave 1.982 mg of iodinated ester 26 as ayellowish oil. Yield 76%. ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.65 (d, J=8.7Hz, 1H), 6.82 (d, J=3.0 Hz, 1H), 6.51 (dd, J₁=8.7 Hz, J₂=3.0 Hz, 1H),4.14 (q, J=7.1 Hz, 2H), 3.76 (s, 3H), 3.00 (t, J=7.9 Hz, 2H), 2.60 (t,J=7.9 Hz, 2H), 1.25 (t, J=7.1 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ ppm:172.4, 160.0, 144.0, 139.9, 115.5, 114.1, 88.6, 60.5, 55.3, 35.9, 34.4,14.2; HRMS (EI) m/z: calcd for C₁₂H₁₅IO₃: 334.0065. found: 334.0082.

Example 77 ethyl3-[5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propionate(27)

Yield 60% (hexane/AcOEt 10:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.75 (d,J=8.2 Hz, 1H), 6.74 (d, J=7.8 Hz, 2H), 4.13 (q, J=7.1 Hz, 2H), 3.80 (s,3H), 3.18 (t, J=8.0 Hz, 2H), 2.57 (t, J=8.0 Hz, 2H), 1.32 (s, 12H), 1.25(t, J=7.1 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 173.3, 161.8, 150.0,138.2, 115.1, 110.8, 83.2, 60.1, 55.0, 37.3, 31.4, 24.8, 14.3; HRMS (EI)m/z: calcd for C₁₈H₂₇BO₅: 333.1987. found: 333.1967.

Example 78 ethyl3-[3′-formyl-4-metoxy-4′-(pyridin-3-yl)biphenyl-2-yl]propionate (28)

Yield 62% (CH₂Cl₂/AcOEt 10:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 10.03 (s,1H), 8.72 (d, J=4.5 Hz, 2H), 7.98 (d, J=1.5 Hz, 1H), 7.77 (dt, J₁=8.1Hz, J₂=2.0 Hz, 1H), 7.63 (dd, J₁=8.1 Hz, J₂=1.8 Hz, 1H), 7.47 (d, J=8.1Hz, 1H), 7.45 (dd, J₁=8.1 Hz, J₂=4.8 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H),6.88 (d, J=3.0 Hz, 1H), 6.84 (dd, J₁=8.1 Hz, J₂=3.0 Hz, 1H), 4.07 (q,J=7.1 Hz, 2H), 3.85 (s, 3H), 2.94 (t, J=7.8 Hz, 2H), 2.49 (t, J=8.0 Hz,2H), 1.19 (t, J=7.2 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 191.2,172.6, 159.5, 150.2, 149.4, 142.0, 140.1, 139.3, 137.2, 134.8, 133.7,132.6, 131.3, 131.0, 129.3, 123.2, 114.7, 111.8, 60.4, 55.3, 35.3, 28.4,14.1; HRMS (EI) m/z: calcd for C₂₄H₂₃NO₄: 389.1627. found: 389.1580;yellowish oil.

Example 79 3-methyl-4-(pyridin-3-yl)phenol (29a)

Yield 75% (CH₂Cl₂/AcOEt 5:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 8.57 (dd,J₁=2.3 Hz, J₂=0.7 Hz, 1H), 8.55 (dd, J₁=5.0 Hz, J₂=1.7 Hz, 1H),7.73-7.66 (m, 1H), 7.38 (ddd, J₁=7.8 Hz, J₂=4.9 Hz, J₃=0.8 Hz, 1H), 7.06(d, J=8.1 Hz, 1H), 6.86 (d, J=2.6 Hz, 1H), 6.83 (dd, J₁=8.1 Hz, J₂=2.6Hz, 1H), 2.21 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 157.1, 149.4,146.7, 138.0, 137.5, 137.0, 131.0, 129.2, 123.4, 117.6, 113.4, 20.5;HRMS (EI) m/z: calcd for C₁₂H₁₁NO: 186.0919 (M+1). found: 186.0920.

Example 80 4′-methoxy-2,3′-dimethylbiphenyl-4-ol (29b)

Yield 63% (hexane/AcOEt 10:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.11 (d,J=8.0 Hz, 3H), 6.89 (dd, J₁=6.9, J₂=2.1 Hz, 1H), 6.73 (ddd, J₁=8.1 Hz,J₂=2.7 Hz, J₃=0.5 Hz, 1H), 6.77 (dd, J₁=2.2 Hz, 0.5 Hz, 1H), 5.42 (s,1H), 3.90 (s, 3H), 2.29 (s, 3H), 2.26 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δppm: 156.4, 154.3, 137.1, 134.5, 133.6, 131.7, 131.0, 127.6, 126.1,116.8, 112.6, 109.6, 55.4, 20.6, 16.2; HRMS (EI) m/z: calcd forC₁₅H₁₆O₂: 227.1072 (M−1). found: 227.1068.

Example 81 3-methyl-4-(pyridin-3-yl)phenyl trifluoromethanesulfonate(30a)

Yield 55% (CH₂Cl₂/AcOEt 5:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 8.63 (dd,J₁=4.9 Hz, J₂=1.7 Hz, 1H), 8.56 (dd, J₁=2.3 Hz, J₂=0.9 Hz, 1H), 7.62(ddd, J₁=7.8 Hz, J₂=2.3 Hz, J₃=1.7 Hz, 1H), 7.37 (ddd, J₁=7.8 Hz, J₂=4.9Hz, J₃=0.9 Hz, 1H), 7.28 (d, J=8.3 Hz, 1H), 7.21 (d, J=2.6 Hz, 1H), 7.18(dd, J₁=8.3 Hz, J₂=2.6 Hz, 1H), 2.29 (s, 3H); ¹⁹F NMR (282 MHz, CDCl₃) δppm: −72.9 (s, 3F); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 149.6, 149.0, 148.8,138.6, 138.5, 136.3, 135.6, 131.5, 123.1, 123.0, 118.8, 118.7 (q,¹J=320.7 Hz), 20.5; HRMS (EI) m/z: calcd for C₁₃H₁₀F₃NO₃S: 318.0412(M+1). found: 318.0419.

Example 82 4′-methoxy-2-methylbiphenyl-4-yl trifluoromethanesulfonate(30b)

Yield 97% (hexane/AcOEt 50:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.27 (d,J=8.4 Hz, 1H), 7.17 (d, J=2.6 Hz, 1H), 7.15-7.05 (m, 3H), 6.89 (d, J=8.5Hz, 1H), 3.89 (s, 3H), 2.32 (s, 3H), 2.82 (s, 3H); ¹⁹F NMR (282 MHz,CDCl₃) δ ppm: −72.96 (s, 3F). −73.15 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δppm: 157.2, 148.2, 142.2, 138.3, 132.0, 131.4, 131.3, 127.4, 126.5,122.6, 118.8 (q, ¹J=318.7 Hz), 118.3, 109.6, 55.3, 20.7, 16.2.

Example 83 ethyl3-[4,4″-dimethoxy-3,2′-dimethyl-(1,1;4′,1″)terphenyl-2″-yl]propionate(31)

Yield 25% (hexane/AcOEt 20:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.26-7.11(m, 6H), 6.93-6.88 (m, 1H), 6.86 (d, J=2.5 Hz, 1H), 6.82 (dd, J₁=8.3 Hz,J₂=2.7 Hz, 1H), 4.10 (q, J=7.1 Hz, 2H), 3.89 (s, 3H), 3.85 (s, 3H), 2.99(t, J=8.0 Hz, 2H), 2.50 (t, J=8.0 Hz, 2H), 2.33 (s, 3H), 2.29 (s, 3H),1.22 (t, J=7.1 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 172.9, 158.8,156.7, 140.1, 139.7, 139.4, 135.1, 134.5, 133.7, 131.6, 131.3, 131.3,129.7, 127.5, 126.7, 126.1, 114.5, 111.5, 109.5, 60.3, 55.3, 55.3, 35.5,28.6, 20.7, 16.3, 14.2; HRMS (EI) m/z: calcd for C₂₇H₃₀O₄: 441.2042(M+Na). found: 441.2047.

Example 843-[(4,4″-dimethoxy-3,2′-dimethyl-(1,1′;4′,1″)terphenyl-2″-yl]propionicacid (32)

Yield 97%. ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.25-7.09 (m, 6H), 6.91-6.87(m, 1H), 6.86 (d, J=2.3 Hz, 1H), 6.83 (dd, J₁=8.2 Hz, J₂=2.7 Hz, 1H),3.89 (s, 3H), 3.84 (s, 3H), 2.99 (t, J=8.0 Hz, 2H), 2.54 (t, J=8.0 Hz,2H), 2.32 (s, 3H), 2.29 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 178.5,158.9, 156.7, 140.2, 139.6, 139.0, 135.2, 134.5, 133.6, 131.7, 131.4,131.2, 129.7, 127.5, 126.6, 126.1, 114.5, 111.6, 109.5, 55.3, 55.3,35.1, 29.7, 28.3, 20.7, 16.3; HRMS (EI) m/z: calcd for C₂₅H₂₆O₄:389.1753 (M−1). found: 389.1760.

Example 85 1-(benzyloxy)-3-isopropylbenzene (33)

To a solution of 3-isopropylphenol (953 mg, 7.00 mmol) in anhydrous DMF(20 mL) were added potassium carbonate (1.934 g, 14.00 mmol) and benzylbromide (1.316 g, 7.70 mmol). The reaction mixture was stirred overnightat room temperature, filtered and the solvent was removed under reducedpressure. The resulting crude reaction product was suspended in waterand extracted with AcOEt. The combined organic layers were dried overNa₂SO₄, filtered and the volatiles were removed in vacuo to give 1.583 gof 9. Yield 99%. ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.32-7.51 (m, 5H), 7.25(t, J=7.8 Hz, 1H), 6.80-6.94 (m, 3H), 5.09 (s, 2H), 2.92 (sep, J=6.9 Hz,1H), 1.28 (d, J=6.9 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 158.9,150.6, 137.2, 129.2, 128.5, 127.9, 127.5, 119.2, 113.4, 111.6, 69.9,34.1, 23.9; HRMS (EI) m/z: calcd for C₁₆H₁₈O: 226.1358. found: 226.1350.

Example 86 4-(benzyloxy)-1-bromo-2-isopropylbenzene (34)

To a solution of 33 (452 mg, 2.00 mmol) in CCl₄ (20 mL) were addedN-bromosuccinimide (373 mg, 2.10 mmol) and silica gel (1 g) and themixture was stirred in the dark at room temperature for 36 hours. Then,the mixture was filtered and the filtrates were washed with saturedsolution of sodium thiosulphate (10 mL). The organic phase were driedover Na₂SO₄, filtered and concentrated on vacuo to give 564 mg ofbromoaryl 34. Yield 93%. ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.32-7.51 (m,6H), 6.92 (d, J=3.0 Hz, 1H), 6.68 (dd, J₁=8.7 Hz, J₂=3.0 Hz, 1H), 5.04(s, 2H), 3.31 (sep, J=6.9 Hz, 1H), 1.22 (d, J=6.9 Hz, 6H); ¹³C NMR (75MHz, CDCl₃) δ ppm: 158.4, 148.5, 136.7, 133.2, 128.6, 128.1, 127.5,115.0, 114.0, 113.3, 70.2, 33.0, 22.7; HRMS (EI) m/z: calcd forC₁₆H₁₇BrO: 304.0463. found: 304.0465.

Example 872-[4-(benzyloxy)-2-isopropylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(35)

Yield 45% (hexane/AcOEt 50:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.75 (d,J=8.1 Hz, 1H), 7.33-7.48 (m, 5H), 6.96 (d, J=2.4 Hz, 1H), 6.79 (dd,J₁=8.4 Hz, J₂=2.4 Hz, 1H), 5.10 (s, 2H), 3.75 (sep, J=6.9 Hz, 1H), 1.35(s, 12H), 1.23 (d, J=6.9 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 161.2,158.1, 137.9, 137.0, 128.5, 127.9, 127.5, 112.0, 110.5, 83.1, 69.7,31.3, 24.8, 24.3; HRMS (EI) m/z: calcd for C₂₂H₃₀BO₃: 352.2324. found:352.2281.

Example 88 ethyl (E)-3-[3′-formyl-4-(hydroxybiphenyl)-2-yl]acrylate (36)

Yield 58% (hexane/AcOEt 10:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 9.99 (s,1H), 7.82 (dt, J₁=7.2 Hz, J₂=1.6 Hz, 1H), 7.74 (t, J=1.5 Hz, 1H),7.52-7.55 (m, 1H), 7.45-7.51 (m, 2H), 7.19 (d, J=8.3 Hz, 1H), 7.10 (d,J=2.6 Hz, 1H), 6.89 (dd, J₁=8.3 Hz, J₂=2.6 Hz, 1H), 6.30 (d, J=15.9 Hz,1H), 5.29 (br s, 1H), 4.13 (q, J=7.1 Hz, 2H), 1.20 (t, J=7.1 Hz, 3H);¹³C NMR (75 MHz, CDCl₃) δ ppm: 192.2, 166.7, 155.6, 142.7, 140.7, 136.5,135.9, 134.2, 133.9, 131.8, 130.9, 129.0, 128.6, 120.1, 117.5, 113.2,60.6, 14.2; HRMS (EI) m/z: calcd for C₁₈H₁₆O₄: 296.1049. found:296.1043; white solid, mp: 148-149° C.

Example 89 ethyl(E)-3-[3′-formyl-4-(trifluoromethanosulfonyloxy)biphenyl-2-yl]acrylate(37)

Yield 85% (hexane/AcOEt 10:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 10.07 (s,1H), 7.96 (dt, J₁=7.6 Hz, J₂=1.4 Hz, 1H), 7.83 (t, J=1.4 Hz, 1H), 7.65(t, J=7.6 Hz, 1H), 7.59 (d, J=2.5 Hz, 1H), 7.56 (dt, J₁=8.1 Hz, J₂=1.6Hz, 1H), 7.54 (d, J=15.9 Hz, 1H), 7.47 (d, J=8.5 Hz, 1H), 7.37 (dd,J₁=8.5 Hz, J₂=2.5 Hz, 1H), 6.43 (d, J=15.9 Hz, 1H), 4.21 (q, J=7.1 Hz,2H), 1.28 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, CDCl₃) δ ppm: −73.17 (s,3F); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 191.6, 165.9, 149.2, 141.2, 140.7,139.1, 136.7, 135.4, 135.2, 132.3, 130.4, 129.6, 129.3, 122.4, 122.2,119.6, 118.7 (q, ¹J=318.8 Hz), 60.8, 14.2; HRMS (EI) m/z: calcd forC₁₉H₁₅F₃O₆S: 428.0541. found: 428.0546; white solid, mp: 77-78° C.

Example 90 ethyl(E)-3-[4″-(benzyloxy)-3-formyl-2″-isopropyl-(1,1′;4′,1″)terphenyl-2′-yl]acrylate(38)

Yield 15% (hexane/AcOEt 5:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 10.09 (s,1H), 7.88-7.96 (m, 2H), 7.61-7.72 (m, 5H), 7.33-7.55 (m, 8H), 7.15 (d,J=8.4 Hz, 1H), 7.04 (d, J=2.4 Hz, 1H), 6.88 (dd, J₁=8.4 Hz, J₂=2.4 Hz,1H), 6.40 (d, J=15.6 Hz, 1H), 5.12 (s, 2H), 4.19 (q, J=7.1 Hz, 2H), 3.07(sep, J=6.9 Hz, 1H), 2.26 (t, J=7.1 Hz, 2H), 1.19 (d, J=6.9 Hz, 6H); ¹³CNMR (75 MHz, CDCl₃) δ ppm: 192.0, 177.4, 166.6, 158.8, 148.0, 142.9,142.0, 140.8, 139.5, 137.0, 136.6, 135.7, 132.4, 131.2, 130.9, 130.9,130.1, 129.0, 128.7, 128.6, 128.0, 128.0, 127.6, 120.1, 112.7, 111.5,70.1, 60.5, 29.5, 24.2, 14.2; HRMS (EI) m/z: calcd for C₃₄H₃₂O₄:504.2301. found: 504.2318.

Example 91 ethyl3-[4″-hydroxy-2″-isopropyl-3-methyl-(1,1′;4′,1″)terphenyl-2′-yl]propionate(39)

Yield 82% (hexane/AcOEt 10:1). ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.27-7.36(m, 1H), 7.12-7.24 (m, 6H), 7.08 (d, J=8.4 Hz, 1H), 6.86 (d, J=2.7 Hz,1H), 6.69 (dd, J₁=8.4 Hz, J₂=2.7 Hz, 1H), 5.06 (s, 1H), 4.06 (q, J=7.1Hz, 2H), 3.10 (sep, J=6.9 Hz, 1H), 2.99 (t, J=8.0 Hz, 2H), 2.47 (t,J=8.0 Hz, 2H), 2.42 (s, 3H), 1.18 (t, J=7.2 Hz, 3H), 1.17 (d, J=6.9 Hz,6H); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 173.0, 155.2, 148.2, 141.3, 140.9,140.3, 137.8, 137.4, 133.6, 131.2, 130.1, 130.0, 129.8, 128.1, 127.7,127.4, 126.2, 112.5, 112.3, 60.3, 35.5, 29.5, 28.4, 24.2, 21.5, 14.1;HRMS (EI) m/z: calcd for C₂₇H₃₀O₃: 402.2195. found: 402.2197.

Biological Activity of Q₂ Peptidomimetics

Example 92

Goodpasture antigen-binding protein (GPBP) is a non-conventional Ser/Thrkinase which targets and phosphorylates the non-collagenous (NC1) domainof α3 chain of human type IV collagen [α 3(IV)NC1], known as Goodpastureantigen. GPBP expression has been associated with antibody-mediatedglomerulonephritis, rheumatoid arthritis and drug-resistance cancer. Wehave reported that GPBP self-interacts, that aggregation andautophosphorylation regulate kinase activity, and that the Q₂ peptideinhibits autophosphorylation and GPBP kinase activity (WO 00/50607). TheGPBP kinase inhibitory activity of a number of terphenylic compoundsmimicking Q₂, a peptide representing a critical GPBP motif which isrelevant for GPBP quaternary structure stabilization, have been testedon GPBP autophosphorylation ability The autophosphorylation ability ofGPBP has been used to test the GPBP kinase inhibitor activity of severalterphenylic compounds (Scheme 18) derived from the chemical structure ofQ₂ peptide, which in turn represents GPBP peptidic sequence relevant forself-interaction.

Two hundred nanograms of yeast recombinant FLAG-GPBP were subjected tophosphorylation assays in absence (vehicle) or presence of a 10 μMconcentration of each of the indicated Q₂-peptidomimetic compounds or anintermediate of synthesis used as negative control (C), during 5 min at30° C. Reactions were subjected to SDS-PAGE, Western blot andautoradiography. The bands in the autoradiography were quantified usingImage-Quant TL software. The kinase activity of GPBP in the presence ofthe indicated compounds was referred to the sample containing thevehicle, which was given a value of 100. Table 1 shows the outcome ofFLAG-GPBP auto-phosphorylation assays performed in presence or absenceof the different Q₂-peptidomimetics compounds represented in Scheme 18.

TABLE 1 Relative kinase activity Compound (% referred to vehicle)vehicle 100  1a 34  1b 131  1c 58  2a 90 12a 53 12b 49 15a 79 15b 21 20a61 20b 77 22a 118 22b 44 22c 123 22d 79 22e 129 22f 41 22g 103 22h 4922i 132 22j 50 22k 135 22l 136 24a 73 24b 64 24c 36 32 28 C 96

Example 93 Additional Materials and Methods

Yeast recombinant FLAG-GPBP production and purification were alsoperformed. GPBP autophosphorylation assay times were limited to 10 minat 30° C.

It is understood that the examples and embodiments described herein arefor illustrative purposes only. Unless clearly excluded by the context,all embodiments disclosed for one aspect of the invention can becombined with embodiments disclosed for other aspects of the invention,in any suitable combination. It will be apparent to those skilled in theart that various modifications and variations can be made to the presentinvention without departing from the scope of the invention. Thus, it isintended that the present invention cover the modifications andvariations of this invention provided they come within the scope of theappended claims and their equivalents. All publications, patents, andpatent applications cited herein are hereby incorporated herein byreference for all purposes.

What is claimed is:
 1. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein: R is N; R₁ ishydrogen, halogen, hydroxy, C₁-C₆ alkyl, halo(C₁-C₆ alkyl), C₁-C₆alkoxy, halo(C₁-C₆ alkoxy), hydroxy(C₁-C₆ alkyl), (C₁-C₆ alkoxy)C₁-C₆alkyl, amino(C₁-C₆ alkyl), sulfanyl(C₁-C₆ alkyl), or (C₁-C₆alkyl)sulfanyl(C₁-C₆ alkyl); R₂ is C₁-C₆ alkyl, halo(C₁-C₆ alkyl), C₁-C₆alkoxy, halo(C₁-C₆ alkoxy), hydroxy(C₁-C₆ alkyl), (C₁-C₆ alkoxy)C₁-C₆alkyl, formyl(C₀-C₆ alkyl), amino(C₁-C₆ alkyl), sulfanyl(C₁-C₆ alkyl),(C₁-C₆ alkyl)sulfanyl(C₁-C₆ alkyl), —(CH₂)₁₋₅—C(O)OH,—(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy), —(CH₂)₁₋₅—C(O)NH₂, (aryl)C₁-C₆ alkyl, or(heteroaryl)C₁-C₆ alkyl; R₃ is C₁-C₆ alkyl, halo(C₁-C₆ alkyl), C₁-C₆alkoxy, halo(C₁-C₆ alkoxy), hydroxy(C₁-C₆ alkyl), (C₁-C₆ alkoxy)C₁-C₆alkyl, formyl(C₁-C₆ alkyl), amino(C₁-C₆ alkyl), sulfanyl(C₁-C₆ alkyl),(C₁-C₆ alkyl)sulfanyl(C₁-C₆ alkyl), —(CH₂)₁₋₅—C(O)OH,—(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy), —(CH₂)₁₋₅—C(O)NH₂, —(CH₂)₁₋₅—C(O)NH(C₁-C₆alkyl), —(CH₂)₁₋₅—C(O)N(C₁-C₆ alkyl)₂, —CH═CH—C(O)OH, —CH═CH—C(O)(C₁-C₆alkoxy), (aryl)C₁-C₆ alkyl, or (heteroaryl)C₁-C₆ alkyl; and R₄ ishydroxy, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆ alkoxy),benzyloxy, —(CH₂)₁₋₅—C(O)OH, —(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy),—(CH₂)₁₋₅—C(O)NH₂, —(CH₂)₁₋₅—C(O)NH(C₁-C₆ alkyl), —(CH₂)₁₋₅—C(O)N(C₁-C₆alkyl)₂, —CH═CH—C(O)OH, —CH═CH—C(O)(C₁-C₆ alkoxy), —O(CH₂)₁₋₅—C(O)OH,—O(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy), (aryl)C₁-C₆ alkyl, or (heteroaryl)C₁-C₆alkyl.
 2. A compound according to claim 1 having the formula:

wherein: R₁ is hydrogen, halogen, hydroxy, C₁-C₆ alkyl, halo(C₁-C₆alkyl), C₁-C₆ alkoxy, halo(C₁-C₆ alkoxy), hydroxy(C₁-C₆ alkyl), (C₁-C₆alkoxy)C₁-C₆ alkyl, amino(C₁-C₆ alkyl), sulfanyl(C₁-C₆ alkyl), or (C₁-C₆alkyl)sulfanyl(C₁-C₆ alkyl); R₂ is C₁-C₆ alkyl, halo(C₁-C₆ alkyl), C₁-C₆alkoxy, halo(C₁-C₆ alkoxy), hydroxy(C₁-C₆ alkyl), (C₁-C₆ alkoxy)C₁-C₆alkyl, formyl(C₀-C₆ alkyl), amino(C₁-C₆ alkyl), sulfanyl(C₁-C₆ alkyl),(C₁-C₆ alkyl)sulfanyl(C₁-C₆ alkyl), —(CH₂)₁₋₅—C(O)OH,—(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy), or —(CH₂)₁₋₅—C(O)NH₂; R₃ is C₁-C₆ alkyl,halo(C₁-C₆ alkyl), C₁-C₆ alkoxy, halo(C₁-C₆ alkoxy), hydroxy(C₁-C₆alkyl), (C₁-C₆ alkoxy)C₁-C₆ alkyl, formyl(C₁-C₆ alkyl), amino(C₁-C₆alkyl), sulfanyl(C₁-C₆ alkyl), (C₁-C₆ alkyl)sulfanyl(C₁-C₆ alkyl),—(CH₂)₁₋₅—C(O)OH, —(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy), —(CH₂)₁₋₅—C(O)NH₂,—(CH₂)₁₋₅—C(O)NH(C₁-C₆ alkyl), —(CH₂)₁₋₅—C(O)N(C₁-C₆ alkyl)₂,—CH═CH—C(O)OH, or —CH═CH—C(O)(C₁-C₆ alkoxy); and R₄ is hydroxy, halogen,C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆ alkoxy), benzyloxy,—(CH₂)₁₋₅—C(O)OH, —(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy), —(CH₂)₁₋₅—C(O)NH₂,—(CH₂)₁₋₅—C(O)NH(C₁-C₆ alkyl), —(CH₂)₁₋₅—C(O)N(C₁-C₆ alkyl)₂,—CH═CH—C(O)OH, —CH═CH—C(O)(C₁-C₆ alkoxy), —O(CH₂)₁₋₅—C(O)OH, or—O(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy).
 3. A compound according to claim 1,wherein R₁ is hydrogen, halogen, hydroxy, C₁-C₆ alkyl, halo(C₁-C₆alkyl), C₁-C₆ alkoxy, or halo(C₁-C₆ alkoxy); R₂ is C₁-C₆ alkyl,halo(C₁-C₆ alkyl), hydroxy(C₁-C₆ alkyl), (C₁-C₆ alkoxy)C₁-C₆ alkyl,formyl(C₀-C₆ alkyl), amino(C₁-C₆ alkyl), sulfanyl(C₁-C₆ alkyl), or(C₁-C₆ alkyl)sulfanyl(C₁-C₆ alkyl); R₃ is C₁-C₆ alkyl, —(CH₂)₁₋₅—C(O)OH,—(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy), —(CH₂)₁₋₅—C(O)NH₂, —(CH₂)₁₋₅—C(O)NH(C₁-C₆alkyl), —(CH₂)₁₋₅—C(O)N(C₁-C₆ alkyl)₂, —CH═CH—C(O)OH, or—CH═CH—C(O)(C₁-C₆ alkoxy); and R₄ is hydroxy, halogen, C₁-C₆ alkyl,C₁-C₆ alkoxy, halo(C₁-C₆ alkoxy), benzyloxy, —(CH₂)₁₋₅—C(O)OH,—(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy), —(CH₂)₁₋₅—C(O)NH₂, —(CH₂)₁₋₅—C(O)NH(C₁-C₆alkyl), —(CH₂)₁₋₅—C(O)N(C₁-C₆ alkyl)₂, —CH═CH—C(O)OH, —CH═CH—C(O)(C₁-C₆alkoxy), —O(CH₂)₁₋₅—C(O)OH, or —O(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy).
 4. Acompound according to claim 1, wherein R₁ is hydrogen.
 5. A compoundaccording to claim 1, wherein R₂ is C₁-C₆ alkyl, halo(C₁-C₆ alkyl),hydroxy(C₁-C₆ alkyl), formyl(C₀-C₆ alkyl), amino(C₁-C₆ alkyl), orsulfanyl(C₁-C₆ alkyl).
 6. A compound according to claim 5, wherein R₂ isC₁-C₆ alkyl, halo(C₁-C₆ alkyl), or hydroxy(C₁-C₆ alkyl).
 7. A compoundaccording to claim 1, wherein R₃ is C₁-C₆ alkyl, —(CH₂)₁₋₅—C(O)OH,—(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy), —CH═CH—C(O)OH, or —CH═CH—C(O)(C₁-C₆alkoxy).
 8. A compound according to claim 7, wherein R₃ is—(CH₂)₁₋₂—C(O)OH, or —(CH₂)₁₋₂—C(O)(C₁-C₆ alkoxy).
 9. A compoundaccording to claim 1, wherein R₄ is hydroxy, halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, halo(C₁-C₆ alkoxy), or benzyloxy.
 10. A compound according toclaim 9, wherein R₄ is hydroxy or C₁-C₆ alkoxy.
 11. A compound accordingto claim 1, wherein R₁ is hydrogen, halogen, hydroxy, C₁-C₆ alkyl,halo(C₁-C₆ alkyl), C₁-C₆ alkoxy, or halo(C₁-C₆ alkoxy); R₂ is C₁-C₆alkyl, halo(C₁-C₆ alkyl), hydroxy(C₁-C₆ alkyl), (C₁-C₆ alkoxy)C₁-C₆alkyl, formyl(C₀-C₆ alkyl), amino(C₁-C₆ alkyl), sulfanyl(C₁-C₆ alkyl),or (C₁-C₆ alkyl)thio(C₁-C₆ alkyl); R₃ is —(CH₂)₁₋₂—C(O)OH,—(CH₂)₁₋₂—C(O)(C₁-C₆ alkoxy), —(CH₂)₁₋₂—C(O)NH₂, —(CH₂)₁₋₂—C(O)NH(C₁-C₆alkyl), —(CH₂)₁₋₂—C(O)N(C₁-C₆ alkyl)₂, —CH═CH—C(O)OH, —CH═CH—C(O)(C₁-C₆alkoxy); and R₄ is hydroxy, C₁-C₆ alkoxy, halo(C₁-C₆ alkoxy), orbenzyloxy.
 12. A compound according to claim 1, wherein R₁ is hydrogen;R₂ is C₁-C₆ alkyl, halo(C₁-C₆ alkyl), hydroxy(C₁-C₆ alkyl), orformyl(C₁-C₆ alkyl); R₃ is —(CH₂)₁₋₂—C(O)OH, —(CH₂)₁₋₂—C(O)(C₁-C₆alkoxy), or —(CH₂)₁₋₂—C(O)NH₂; and R₄ is hydroxy or C₁-C₆ alkoxy.
 13. Acompound according to claim 1, wherein R₁ is hydrogen; R₂ is C₁-C₆alkyl; R₃ is —(CH₂)₁₋₂—C(O)OH; and R₄ is C₁-C₆ alkoxy.
 14. A compoundaccording to claim 1, wherein R₁ is hydrogen; R₂ is methyl; R₃ is—(CH₂)₂—C(O)OH; and R₄ is methoxy.
 15. A compound according to claim 1,which is:3-[4-hydroxy-3′-(hydroxymethyl)-4′-(pyridine-3-yl)biphenyl-2-yl]propionicacid; (E)-ethyl3-[4-(benzyloxy)-3′-formyl-4′-(pyridine-3-yl)biphenyl-2-yl]acrylate;ethyl3-[4-hydroxy-3′-(hydroxymethyl)-4′-(pyridine-3-yl)biphenyl-2-yl]propionate;ethyl3-[3′-(fluoromethyl)-4-hydroxy-4′-(pyridine-3-yl)biphenyl-2-yl]propionate;3-[3′-(fluoromethyl)-4-hydroxy-4′-(pyridine-3-yl)biphenyl-2-yl]propionicacid; (E)-ethyl3-[4-(benzyloxy)-3′-(difluoromethyl)-4′-(pyridin-3-yl)biphenyl-2-yl]acrylate;ethyl3-[3′-(difluoromethyl)-4-hydroxy-4′-(pyridin-3-yl)biphenyl-2-yl]propionate;3-[3′-(difluoromethyl)-4-hydroxy-4′-(pyridine-3-yl)biphenyl-2-yl]propionicacid; ethyl3-[3′-(hydroxymethyl)-4-metoxy-4′-(pyridine-3-yl)biphenyl-2-yl]propionate;ethyl 3-[4-methoxy-3′-methyl-4′-(pyridine-3-yl)biphenyl-2-yl]propionate;ethyl3-[3′-(fluoromethyl)-4-metoxy-4′-(pyridin-3-yl)biphenyl-2-yl]propionate;ethyl3-[3′-(difluoromethyl)-4-metoxy-4′-(pyridine-3-yl)biphenyl-2-yl]propionate;3-[3′-(hydroxymethyl)-4-methoxy-4′-(pyridine-3-yl)-biphenyl-2-yl]propionicacid; 3-[4-methoxy-3′-methyl-4′-(pyridine-3-yl)biphenyl-2-yl]propionicacid;3-[3′-(fluoromethyl)-4-methoxy-4′-(pyridine-3-yl)-biphenyl-2-yl]propionicacid;3-[3′-(difluoromethyl)-4-methoxy-4′-(pyridine-3-yl)-biphenyl-2-yl]propionicacid; ethyl3-[3′-formyl-4-metoxy-4′-(pyridine-3-yl)biphenyl-2-yl]propionate; or apharmaceutically acceptable salt thereof.
 16. A pharmaceuticalcomposition comprising a compound according to claim 1 and at least onepharmaceutically acceptable carrier, solvent, adjuvant or diluent.
 17. Aprocess for preparing a compound of formula:

or a pharmaceutically acceptable salt thereof, comprising reacting acompound of formula:

with a compound of formula:

wherein R is N; R₁ is hydrogen, halogen, hydroxy, C₁-C₆ alkyl,halo(C₁-C₆ alkyl), C₁-C₆ alkoxy, halo(C₁-C₆ alkoxy), hydroxy(C₁-C₆alkyl), (C₁-C₆ alkoxy)C₁-C₆ alkyl, amino(C₁-C₆ alkyl), sulfanyl(C₁-C₆alkyl), or (C₁-C₆ alkyl)sulfanyl(C₁-C₆ alkyl); R₂ is C₁-C₆ alkyl,halo(C₁-C₆ alkyl), C₁-C₆ alkoxy, halo(C₁-C₆ alkoxy), hydroxy(C₁-C₆alkyl), (C₁-C₆ alkoxy)C₁-C₆ alkyl, formyl(C₀-C₆ alkyl), amino(C₁-C₆alkyl), sulfanyl(C₁-C₆ alkyl), (C₁-C₆ alkyl)sulfanyl(C₁-C₆ alkyl),—(CH₂)₁₋₅—C(O)OH, —(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy), —(CH₂)₁₋₅—C(O)NH₂,(aryl)C₁-C₆ alkyl, or (heteroaryl)C₁-C₆ alkyl; R₃ is C₁-C₆ alkyl,halo(C₁-C₆ alkyl), C₁-C₆ alkoxy, halo(C₁-C₆ alkoxy), hydroxy(C₁-C₆alkyl), (C₁-C₆ alkoxy)C₁-C₆ alkyl, formyl(C₁-C₆ alkyl), amino(C₁-C₆alkyl), sulfanyl(C₁-C₆ alkyl), (C₁-C₆ alkyl)sulfanyl(C₁-C₆ alkyl),—(CH₂)₁₋₅—C(O)OH, —(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy), —(CH₂)₁₋₅—C(O)NH₂,—(CH₂)₁₋₅—C(O)NH(C₁-C₆ alkyl), —(CH₂)₁₋₅—C(O)N(C₁-C₆ alkyl)₂,—CH═CH—C(O)OH, —CH═CH—C(O)(C₁-C₆ alkoxy), (aryl)C₁-C₆ alkyl, or(heteroaryl)C₁-C₆ alkyl; and R₄ is hydroxy, halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, halo(C₁-C₆ alkoxy), benzyloxy, —(CH₂)₁₋₅—C(O)OH,—(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy), —(CH₂)₁₋₅—C(O)NH₂, —(CH₂)₁₋₅—C(O)NH(C₁-C₆alkyl), —(CH₂)₁₋₅—C(O)N(C₁-C₆ alkyl)₂, —CH═CH—C(O)OH, —CH═CH—C(O)(C₁-C₆alkoxy), —O(CH₂)₁₋₅—C(O)OH, —O(CH₂)₁₋₅—C(O)(C₁-C₆ alkoxy), (aryl)C₁-C₆alkyl, or (heteroaryl)C₁-C₆ alkyl; and each R″ is independentlyhydrogen, or C₁-C₆ alkyl, or two R″ together with the atoms to whichthey are attached form a dioxaborolanyl or dioxaborinanyl ring, eachoptionally subsituted with C₁-C₆ alkyl.
 18. A compound according toclaim 1, wherein R₁ is hydrogen; R₂ is C₁-C₆ alkyl, halo(C₁-C₆ alkyl),or hydroxy(C₁-C₆ alkyl); R₃ is —(CH₂)₂—C(O)OH; and R₄ is methoxy.